3-(5-substituted-4-oxoquinazolin-3(4h)-yl)-3-deuteropiperidine-2,6-dione derivatives and compositions comprising and methods of using the same

ABSTRACT

The invention provides 3-deuterium-enriched 3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-diones, deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salt forms thereof, and methods of treatment using the same, such as in the treatment of cancer, an immune-related disease, or an inflammatory disease.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/222,280, filed Dec. 17, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/379,908, filed Dec. 15, 2016, which is acontinuation of U.S. patent application Ser. No. 14/154,743, filed Jan.14, 2014, which claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. No. 61/786,024, filed Mar. 14, 2013, and U.S.Provisional Patent Application Ser. No. 61/752,055, filed Jan. 14, 2013;the contents of each of which are hereby incorporated by reference.

BACKGROUND

Compounds such as3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione(Formula A) and3-(2,5-di-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione (FormulaB) and other derivatives in this family are currently being studied asanti-proliferative, immunomodulatory, and anti-angiogenic agents.

The above compounds are described in U.S. Pat. Nos. 7,635,700 and8,492,395; U.S. Patent Application Publication Nos. 2009/0082375,2010/0016342, 2012/0230982, and 2012/0232100; and International PatentApplication Publication No. WO 2012/125475; the contents of which arehereby incorporated by reference.

The compounds of Formula A and B, because of the asymmetric carbon onthe glutarimide ring (i.e., the piperidine-2,6-dione ring), are aracemic mixture of R and S stereoisomers. The hydrogen at the 3-positionis acidic due to the presence of the adjacent carbonyl moiety, therebymaking it difficult to prevent racemization of the two stereoisomers anddifficult to determine if one of the stereoisomers is superior to theother.

The present invention provides new compounds that are resistant toracemization at their stereogenic center, and are useful in thetreatment of various medical disorders.

SUMMARY OF THE INVENTION

Accordingly, described herein are 3-deuterium-enriched3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-diones (e.g.,3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-diones)and stereoisomers, solvates, and pharmaceutically acceptable saltsthereof.

Another aspect provided herein is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and at least one of thedeuterium-enriched compounds of the invention or a stereoisomer,solvate, or pharmaceutically acceptable salt thereof.

Another aspect is a method for treating, preventing, and/or managingangiogenesis and/or a cytokine related disorder, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the deutero-compounds of theinvention or a stereoisomer, solvate, or pharmaceutically acceptablesalt thereof.

Another aspect is a method for treating, preventing, and/or managing acancer, comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of thedeutero-compounds of the invention or a stereoisomer, solvate, orpharmaceutically acceptable salt thereof.

Another aspect is a method for treating, preventing, and/or managing adisease associated with lymphocytic activity, including activity of Bcells and/or T cells, e.g., immune-related diseases or inflammatorydiseases, comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of thedeutero-compounds of the invention or a stereoisomer, solvate, orpharmaceutically acceptable salt thereof.

Also provided are novel 3-deuterium-enriched3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-diones or astereoisomer, solvate, or pharmaceutically acceptable salt thereof foruse in therapy.

Another aspect is the use of novel 3-deuterium-enriched3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-diones or astereoisomer, solvate, or pharmaceutically acceptable salt thereof forthe manufacture of a medicament (e.g., for the treatment of angiogenesisand/or a cytokine related disorder). In certain instances, the treatmentis for cancer, an immune-related disease, or an inflammatory disease.

These and other aspects, which will become apparent during the followingdetailed description, have been achieved by the inventor's discovery of3-deuterium-enriched3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-diones.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing in vitro stability data for(−)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione(designated “h−”) in human plasma, as described in Example 3, where theabbreviation “calc” indicates results from fitting experimental data tokinetic differential equations.

FIG. 2 is a graph showing in vitro stability data for(+)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione(designated “h+”) in human plasma, as described in Example 3, where theabbreviation “calc” indicates results from fitting experimental data tokinetic differential equations.

FIG. 3 is a graph showing in vitro stability data for racemic3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(which is a 1:1 mixture of the (−)-deuterated enantiomer (i.e., “d−”)and (+)-deuterated enantiomer (i.e., “d+”) and which is designated“d-rac”) in human plasma, as described in Example 3. The abbreviationsd2-e1 and d2-e2 correspond to a low amount of the enantiomers of3,5-bis-deuterated3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione. Theabbreviation “calc” indicates results from fitting experimental data tokinetic differential equations.

FIG. 4 is a graph showing in vitro stability data for(−)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione(designated “h−”) in mouse plasma, as described in Example 3, where theabbreviation “calc” indicates results from fitting experimental data tokinetic differential equations.

FIG. 5 is a graph showing in vitro stability data for(+)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione(designated “h+”) in mouse plasma, as described in Example 3, where theabbreviation “calc” indicates results from fitting experimental data tokinetic differential equations.

FIG. 6 is a graph showing in vitro stability data for racemic3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(which is a 1:1 mixture of the (−)-deuterated enantiomer (i.e., “d−”)and (+)-deuterated enantiomer (i.e., “d+”) and which is designated“d-rac”) in mouse plasma, as described in Example 3. The abbreviationd2-e1 and d2-e2 correspond to a low amount of the enantiomers of3,5-bis-deuterated3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione. Theabbreviation “calc” indicates results from fitting experimental data tokinetic differential equations.

FIG. 7 is a graph of plasma concentration ofrac-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione(i.e., a 1:1 mixture of the (−)-enantiomer (abbreviated “h−”) and the(+)-enantiomer (abbreviated “h+”)) following oral administration ofrac-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione(30 mg/kg) to mice, as described in Example 4.

FIG. 8 is a graph of plasma concentration of(−)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(abbreviated “d−”) following oral administration of(−)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(15 mg/kg) to mice, as described in Example 4.

FIG. 9 is a graph of plasma concentration of(+)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(abbreviated “d+”) following oral administration of(+)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4)-yl)-(3-²H)-piperidine-2,6-dione(15 mg/kg) to mice, as described in Example 4.

FIG. 10 is a graph showing average H929 xenograft tumor volume (±SEM) asa function of time in female CB.17 SCID mice treated daily by oralgavage with vehicle, racemic3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione(abbreviated “h-rac”),(+)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(abbreviated “d+”), or(−)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(abbreviated “d-”); where data were analyzed by 2-way ANOVA followed bypost-hoc analysis using Bonferroni's test against vehicle group(*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001), as described in Example5.

DETAILED DESCRIPTION

Deuterium (D or ²H) is a stable, non-radioactive isotope of hydrogen andhas an atomic weight of 2.014. Hydrogen naturally occurs as a mixture ofthe isotopes ¹H (hydrogen or protium), D (²H or deuterium), and T (H ortritium). The natural abundance of deuterium is 0.015%. One of ordinaryskill in the art recognizes that in all chemical compounds with a Hatom, the H atom actually represents a mixture of H and D, with about0.015% being D. Thus, compounds with a level of deuterium that has beenenriched to be greater than its natural abundance of 0.015%, should beconsidered unnatural and, as a result, novel over their non-enrichedcounterparts. Thus, the present invention relates to adeuterium-enriched compound or compounds whose enrichment is greaterthan naturally occurring deuterated molecules.

All percentages given for the amount of deuterium present are molepercentages. Further, when a variable is not accompanied by adefinition, the previous definition of the variable controls.

Unless indicated otherwise, when a D is specifically recited at aposition or is shown in a formula, this D represents a mixture ofhydrogen and deuterium where the amount of deuterium is about 100%(i.e., the abundance of deuterium is from 90% to 100%). In certainaspects, the abundance of deuterium is from 97% to 100%).

The 3-deuterium group (i.e., the Z group) in the present compounds meansthat the compounds have been isotopically enriched at the 3-position andare different and distinct from the corresponding non-enriched compound.

Compound refers to a quantity of molecules that is sufficient to beweighed, tested for its structural identity, and to have a demonstrableuse (e.g., a quantity that can be shown to be active in an assay, an invitro test, or in vivo test, or a quantity that can be administered to apatient and provide a therapeutic benefit).

I. Exemplary Deuterium-Enriched Compounds

One aspect of the invention provides a deuterium-enriched compound ofFormula I:

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

Z is H or D, provided that the abundance of deuterium in Z is at least30%;

R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ are independently selected from H andD;

R⁶ is selected from: H; D; —(CH₂)_(n)OH; phenyl; —O(C₁-C₆)alkyl; and(C₁-C₆)alkyl optionally substituted with one or more halo;

R¹⁰ is selected from: H; D; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyl optionallysubstituted with one or more halo; (C₁-C₆)alkoxy optionally substitutedwith one or more halo; and —(CH₂)_(n)NR^(a);

R^(a) is selected from: H; D; (C₁-C₆)alkyl optionally substituted withone or more halo; —(CH₂)_(n)-(6 to 10 membered aryl); —C(O)(CH₂)_(n)-(6to 10 membered aryl); —C(O)(CH₂)_(n)-(6 to 10 membered heteroaryl);—C(O)(C₁-C₈)alkyl optionally substituted with one or more halo;—C(O)(CH₂)_(n)—(C₃-C₁₀-cycloalkyl); —C(O)(CH₂)_(n)—NR^(b)R^(c),—C(O)(CH₂)_(n)—O—(C₁-C₆)alkyl; and, —C(O)(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10membered aryl); wherein the aryl and heteroaryl are optionallysubstituted with one or more groups selected from: halo; —SCF₃;(C₁-C₆)alkyl optionally substituted with one or more halo; and(C₁-C₆)alkoxy optionally substituted with one or more halo;

R^(b) and R^(c) are each independently selected from: H; D; (C₁-C₆)alkyloptionally substituted with one or more halo; (C₁-C₆)alkoxy optionallysubstituted with one or more halo; and 6 to 10 membered aryl; the arylbeing optionally substituted with one or more groups selected from:halo; (C₁-C₆)alkyl optionally substituted with one or more halo; and(C₁-C₆)alkoxy optionally substituted with one or more halo;

alternatively, R¹⁰ is selected from R^(10a), R^(10b), and R^(10c);

R^(10a) is selected from: H; D; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyloptionally substituted with one or more halo; and (C₁-C₆)alkoxyoptionally substituted with one or more halo;

R^(10b)=—(CH₂)_(n)—NHR^(d);

R^(10c)=—(CH₂)_(n)—NHR^(g);

R^(d) is selected from: H; D; —(C₁-C₆)alkyl optionally substituted withone or more halo; —C(O)(C₁-C₈)alkyl optionally substituted with one ormore halo; —C(O)(CH₂)_(n)(C₃-C₁₀-cycloalkyl); —C(O)(CH₂)_(n)NR^(e)R^(f);and, —C(O)(CH₂)_(n)O(C₁-C₆)alkyl.

R^(e) and R^(f) are each independently selected from: hydrogen;(C₁-C₆)alkyl optionally substituted with one or more halo; and(C₁-C₆)alkoxy optionally substituted with one or more halo;

R^(g) is selected from: —C(O)(CH₂)_(n)NR^(h); —(CH₂)_(n)-(6 to 10membered aryl); —C(O)(CH₂)_(n)-(6 to 10 membered aryl);—C(O)(CH₂)_(n)-(6 to 10 membered heteroaryl); and,—C(O)(CH₂)_(n)O(CH₂)_(n)-(6 to 10 membered aryl), wherein the aryl andheteroaryl are optionally substituted with one or more groups selectedfrom: halo; —SCF₃; (C₁-C₆)alkyl optionally substituted with one or morehalo; and, (C₁-C₆)alkoxy substituted with one or more halo;

R^(h) is selected from: 6 to 10 membered aryl optionally substitutedwith one or more groups selected from: halo; (C₁-C₆)alkyl optionallysubstituted with one or more halo; and, (C₁-C₆)alkoxy optionallysubstituted with one or more halo;

n is independently selected from selected from 0, 1, and 2; and

a hydrogen atom present in any substituent is optionally replaced by D.

In another aspect, n is 0. In another aspect, n is 1. In another aspect,n is 2.

In certain embodiments, the compound is a compound of Formula I or apharmaceutically acceptable salt or stereoisomer thereof.

Another aspect of the invention provides a deuterium-enriched compoundof Formula I-A:

and pharmaceutically acceptable salts and stereoisomers thereof,wherein:

Z is H or D, provided that the abundance of deuterium in Z is at least30%;

R_(1-A) and R_(2-A) are independently selected from H and D.

In certain embodiments, R_(1-A) and R_(2-A) are H. In certainembodiments, the compound is the (−)-enantiomer. In certain otherembodiments, the compound is the (+)-enantiomer.

In certain embodiments, the deuterium-enriched compound is one of thegeneric formulae described herein wherein the abundance of deuterium inZ is selected from: (a) at least 40%, (b) at least 50%, (c) at least60%, (d) at least 70%, (e) at least 80%, (f) at least 90%, (g) at least95%, (h) at least 97%, and (i) about 100%. Additional examples of theabundance of deuterium in Z include 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99 to about 100%.

Deuterium-enriched compounds characterized according to theirstereochemical purity are provided. The stereochemical purity ofcompounds having one stereocenter can be characterized as enantiomericexcess (ee). Enantiomeric excess can be calculated using the formula:

e e(%) = (R − S)/(R + S)^(*)100

where R and S are the amounts of (R) and (S) enantiomers in the mixture.

For compounds having two or more stereocenters, the stereochemicalpurity (sp) refers to the percentage of 1 of the 4 or more possiblestereoisomers being present. For a compound with two stereocenters, thestereomeric purity can be calculated using the formula:

s p(%) = %  Isomer  1 − (%  Isomer  2 + %  Isomer  3 + %  Isomer  4)

where % Isomer # is the weight (e.g., mole) % of one of the isomers inthe mixture.

In another aspect, the present invention provides a compound having anenantiomeric excess, with respect to the C—Z carbon, of at least 5%.Exantiomeric excess, with respect to the C—Z carbon (i.e., 3-carbon ofthe glutarimide), refers only to the stereomeric purity around thiscarbon, regardless of whether or not additional stereocenters arepresent in the compound.

In another aspect, the present invention provides deuterium-enrichedcompounds wherein the enantiomeric excess is selected from: (a) at least10%, (b) at least 20%, (c) at least 30%, (d) at least 40%, (e) at least50%, (f) at least 60%, (g) at least 70%, (h) at least 80%, (i) at least90%, (j) at least 95%, (k) at least 97%, (1) at least 98%, and (m) atleast 99%. Additional examples of the stereoisomeric purity include anenantiomeric excess of at least 10, 11, 12, 13, 14, 15, 16, 17 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, or 99%.

In another aspect, the present invention provides a compound havingstereomeric purity of at least 5%.

In another aspect, the present invention provides deuterium-enrichedcompounds wherein the stereomeric purity is selected from: (a) at least10%, (b) at least 20%, (c) at least 30%, (d) at least 40%, (e) at least50%, (f) at least 60%, (g) at least 70%, (h) at least 80%, (i) at least90%, (j) at least 95%, (k) at least 97%, (1) at least 98%, and (m) atleast 99%. Additional examples of the stereoisomeric purity include atleast 10, 11, 12, 13, 14, 15, 16, 17 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,or 99%.

In yet other embodiments, the deuterium-enriched compound is a compoundof Formula I-B:

and pharmaceutically acceptable salts and stereoisomers thereof, whereinR_(1-A) and R_(2-A) are independently selected from H and D.

In certain embodiments, R_(1-A) and R_(2-A) are H. In certainembodiments, the compound is the (−)-enantiomer. In certain otherembodiments, the compound is the (+)-enantiomer.

In yet other embodiments, the deuterium-enriched compound is a compoundof Formula I-C:

and pharmaceutically acceptable salts and stereoisomers thereof.

In certain embodiments, the compound is the (−)-enantiomer. In certainother embodiments, the compound is the (+)-enantiomer.

In yet other embodiments, the deuterium-enriched compound is a compoundof Formula I-D having an optical purity of at least 75% enantiomericexcess:

and pharmaceutically acceptable salts thereof, wherein R_(1-A) andR_(2-A) are independently selected from H and D.

In certain embodiments, R_(1-A) and R_(2-A) are H. In certainembodiments, the compound has an optical purity of at least 85%enantiomeric excess, 90% enantiomeric excess, 95% enantiomeric excess,or 98% enantiomeric excess.

In yet other embodiments, the deuterium-enriched compound is a compoundof Formula I-E having an optical purity of at least 75% enantiomericexcess:

and pharmaceutically acceptable salts thereof.

In certain embodiments, the compound has an optical purity of at least85% enantiomeric excess, 90% enantiomeric excess, 95% enantiomericexcess, or 98% enantiomeric excess.

In yet other embodiments, the deuterium-enriched compound is a compoundof Formula I-F having an optical purity of at least 75% enantiomericexcess:

and pharmaceutically acceptable salts thereof, wherein R_(1-A) andR_(2-A) are independently selected from H and D.

In certain embodiments, R_(1-A) and R_(2-A) are H. In certainembodiments, the compound has an optical purity of at least 85%enantiomeric excess, 90% enantiomeric excess, 95% enantiomeric excess,or 98% enantiomeric excess.

In yet other embodiments, the deuterium-enriched compound is a compoundof Formula I-G having an optical purity of at least 75% enantiomericexcess:

and pharmaceutically acceptable salts thereof.

In certain embodiments, the compound has an optical purity of at least85% enantiomeric excess, 90% enantiomeric excess, 95% enantiomericexcess, or 98% enantiomeric excess.

In another aspect, the present invention provides deuterium-enrichedcompounds of formula Ia or Ib:

and pharmaceutically acceptable salts and solvates thereof, wherein Z,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are as defined above forformula I.

In another aspect, the present invention provides deuterium-enrichedcompounds of formula Ia or Ib:

and pharmaceutically acceptable salts and solvates thereof, wherein Z,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are as defined above forformula I, and wherein the compound has an enantiomeric excess, withrespect to the C—Z carbon, of at least 5%.

In another aspect, the present invention provides deuterium-enrichedcompounds of formula Ic or Id:

and pharmaceutically acceptable salts and solvates thereof, wherein Z,R⁶, and R¹⁰ are as defined above for formula I.

In another aspect, the present invention provides deuterium-enrichedcompounds of formula Ic or Id:

and pharmaceutically acceptable salts and solvates thereof, wherein Z,R⁶, and R¹⁰ are as defined above for formula I, and wherein the compoundhas an enantiomeric excess, with respect to the C—Z carbon, of at least5%.

In another aspect, the present invention provides deuterium-enrichedcompounds of formula Ie or If:

and pharmaceutically acceptable salts and solvates thereof, wherein R⁶and R¹⁰ are as defined above for formula I.

In another aspect, the present invention provides deuterium-enrichedcompounds of formula Ie or If:

and pharmaceutically acceptable salts and solvates thereof, wherein R⁶and R¹⁰ are as defined above for formula I, and wherein the compound hasan enantiomeric excess, with respect to the C-D carbon, of at least 5%.

In another aspect, the present invention provides deuterium-enrichedcompounds of formulae Ia-If, wherein R¹⁰═R^(10a) (compounds IIa-IIf)),and pharmaceutically acceptable salts and solvates thereof.

In another aspect, R¹⁰═R^(10a) and R⁶ is H.

In another aspect, R¹⁰═R^(10a) and R⁶ is —(CH₂)_(n)OH or hydroxyl. Inanother aspect, R¹⁰═R^(10a) and R⁶ is phenyl. In another aspect,R¹⁰═R^(10a) and R⁶ is —O(C₁-C₆)alkyl optionally substituted with one ormore halo.

In another aspect, R¹⁰═R^(10a) and R⁶ is (C₁-C₆)alkyl optionallysubstituted with one or more halo.

In another aspect, R¹⁰═R^(10a) and R⁶ is methyl. In another aspect,R¹⁰═R^(10a) and R⁶ is —CF₃.

In another aspect, R^(10a) is H. In another aspect, R^(10a) is halo.

In another aspect, R^(10a) is (C₁-C₆)alkyl optionally substituted withone or more halo.

In another aspect, R^(10a) is —(CH₂)_(n)OH or hydroxyl.

In another aspect, R^(10a) is (C₁-C₆)alkoxy optionally substituted withone or more halo.

In another aspect, R^(10a) is methyl. In another aspect, R^(10a) ismethoxy. In another aspect, R^(10a) is —CF₃. In another aspect, R^(10a)is F or Cl.

In another aspect, the present invention provides deuterium-enrichedcompounds of formulae IIa or IIb:

wherein the compound is selected from:

a. R^(10a)═CH₃ and R⁶═H;b. R^(10a)═CH₃ and R⁶=D;c. R^(10a)═CH₃ and R⁶═OH;d. R^(10a)═CH₃ and R⁶═CH₃;e. R^(10a)═CH₃ and R⁶═CD₃;f. R^(10a)═CH₃ and R⁶═CH₂CH₃;g. R^(10a)═CH₃ and R⁶═CD₂CD₃;h. R^(10a)═CH₃ and R⁶═CH₂CH₂CH₃;i. R^(10a)═CH₃ and R⁶═CD₂CD₂CD₃;j. R^(10a)═CH₃ and R⁶═CF₃;k. R^(10a)═CH₃ and R⁶=phenyl;l. R^(10a)═CH₃ and R⁶=d₅-phenyl;m. R^(10a)═CD₃ and R⁶═H;n. R^(10a)═CD₃ and R⁶=D;o. R^(10a)═CD₃ and R⁶═OH;p. R^(10a)═CD₃ and R⁶═CH₃;q. R^(10a)═CD₃ and R⁶═CD₃;r. R^(10a)═CD₃ and R⁶═CH₂CH₃;s. R^(10a)═CD₃ and R⁶═CD₂CD₃;t. R^(10a)═CD₃ and R⁶═CH₂CH₂CH₃;u. R^(10a)═CD₃ and R⁶═CD₂CD₂CD₃;v. R^(10a)═CD₃ and R⁶═CF₃;w. R^(10a)═CD₃ and R⁶=phenyl;x. R^(10a)═CD₃ and R⁶=d₅-phenyl;y. R⁶═CH₃ and R^(10a)═OCH₃;z. R⁶═CH₃ and R^(10a)=OCD₃;aa. R⁶═CH₃ and R^(10a)═F;bb. R⁶═CH₃ and R^(10a)═Cl;cc. R⁶═CH₃ and R^(10a)═CF₃;dd. R⁶═CD₃ and R^(10a)═OCH₃;ee. R⁶═CD₃ and R^(10a)=OCD₃;ff. R⁶═CD₃ and R^(10a)═F;gg. R⁶═CD₃ and R^(10a)═Cl;hh. R⁶═CD₃ and R^(10a)═CF₃;ii. R⁶═H and R^(10a)═Cl; and,jj. R⁶=D and R^(10a)═Cl.

and pharmaceutically acceptable salts and solvates thereof, wherein:

Z is H or D, provided that the abundance of deuterium in Z is at least30%;

R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ are independently selected from H andD; and wherein the compound of formulae IIa or IIb has an enantiomericexcess, with respect to the C—Z carbon, of at least 5%.

In another aspect, the present invention provides deuterium-enrichedcompounds selected from:

wherein:

wherein:a. R⁶═H;b. R⁶═OH;c. R⁶═CH₂CH₃;d. R⁶═CH₂CH₂CH₃;e. R⁶═CF₃;f. R⁶=phenyl;g. R⁶═CH₃;

wherein:

h. R^(10a)═OCH₃;i. R^(10a)═F;j. R^(10a)═Cl;k. R^(10a)═CF₃;l.

and pharmaceutically acceptable salts and solvates thereof, wherein thecompound has an enantiomeric excess, with respect to the C—Z carbon, ofat least 5%.

In another aspect, the present invention provides deuterium-enrichedcompounds of formulae Ia-If, wherein R¹⁰═R^(10b) (compounds IIIa-IIIf)),and pharmaceutically acceptable salts and solvates thereof.

In another aspect, R^(d) is H.

In another aspect, R^(d) is (C₁-C₆)alkyl optionally substituted with oneor more halo.

In another aspect, R^(d) is —C(O)(C₁-C₈)alkyl.

In another aspect, R^(d) is —C(O)(CH₂)_(n)(C₃-C₁₀-cycloalkyl).

In another aspect, R^(d) is —C(O)(CH₂)_(n)NR^(e)R^(f).

In another aspect, R^(d) is —C(O)(CH₂)_(n)O(CH₂)_(n)(C₁-C₆)alkyl.

In another aspect, R^(d) is —C(O)(C₁-C₆)alkyl.

In another aspect, R^(d) is NH₂.

In another aspect, R^(d) is —C(O)CH₂O(C₁-C₆)alkyl.

In another aspect, R¹⁰═R^(10b) and R⁶ is H.

In another aspect, R¹⁰═R^(10b) and R⁶ is —(CH₂)_(n)OH or hydroxyl.

In another aspect, R¹⁰═R^(10b) and R⁶ is phenyl.

In another aspect, R¹⁰═R^(10b) and R⁶ is —O(C₁-C₆)alkyl optionallysubstituted with one or more halo.

In another aspect, R¹⁰═R^(10b) and R⁶ is (C₁-C₆)alkyl optionallysubstituted with one or more halo.

In another aspect, R¹⁰═R^(10b) and R⁶ is methyl.

In another aspect, the present invention provides deuterium-enrichedcompounds of formulae IIIa or IIIb:

wherein the compound is selected from:

a. R⁶═CH₃ and R^(10b)═NH₂;b. R⁶═CH₃ and R^(10b)═NHC(O)CH₂OCH₃;c. R⁶═CH₃ and R^(10b)═NHC(O)CH₃;d. R⁶═CH₃ and R^(10b)═NHC(O)-cyclopropyl;e. R⁶═CH₃ and R^(10b)═NHC(O)(CH₂)₅CH₃;f. R⁶═CH₃ and R^(10b)═NHC(O)CH₂OCH₂CH₃;g. R⁶═CH₃ and R^(10b)═NHC(O)CH₂N(CH₃)₂;h. R⁶═CH₃ and R^(10b)═NHC(O)CH₂Cl;i. R⁶═CH₃ and R^(10b)═NHC(O)OCH₂CH₃;j. R⁶═CH₃ and R^(10b)═CH₂NHC(O)OC(CH₃)₃;k. R⁶═CH₃ and R^(10b)═CH₂NHC(O)CH₃;l. R⁶═CH₃ and R^(10b)═CH₂NHC(O)(CH₂)₅CH₃;m. R⁶═CH₃ and R^(10b)═CH₂NHC(O)CH₂C(CH₃)₃;n. R⁶═CH₃ and R^(10b)═CH₂NHC(O)-cyclopropyl;o. R⁶═CH₃ and R^(10b)═CH₂NHC(O)CH₂N(CH₃)₂;p. R⁶═CD₃ and R^(10b)═NH₂;q. R⁶═CD₃ and R^(10b)═NHC(O)CH₂OCH₃;r. R⁶═CD₃ and R^(10b)═NHC(O)CH₃;s. R⁶═CD₃ and R^(10b)═NHC(O)-cyclopropyl;t. R⁶═CD₃ and R^(10b)═NHC(O)(CH₂)₅CH₃;u. R⁶═CD₃ and R^(10b)═NHC(O)CH₂OCH₂CH₃;v. R⁶═CD₃ and R^(10b)═NHC(O)CH₂N(CH₃)₂;w. R⁶═CD₃ and R^(10b)═NHC(O)CH₂Cl;x. R⁶═CD₃ and R^(10b)═NHC(O)OCH₂CH₃;y. R⁶═CD₃ and R^(10b)═CH₂NHC(O)OC(CH₃)₃;z. R⁶═CD₃ and R^(10b)═CH₂NHC(O)CH₃;aa. R⁶═CD₃ and R^(10b)═CH₂NHC(O)(CH₂)₅CH₃;bb. R⁶═CD₃ and R^(10b)═CH₂NHC(O)CH₂C(CH₃)₃;cc. R⁶═CD₃ and R^(10b)═CH₂NHC(O)-cyclopropyl;dd. R⁶═CD₃ and R^(10b)═CH₂NHC(O)CH₂N(CH₃)₂;ee. R⁶═CH₃ and R^(10b)═NHC(O)CD₂OCD₃;ff. R⁶═CH₃ and R^(10b)═NHC(O)CD₃;gg. R⁶═CH₃ and R^(10b)═NHC(O)-d₅-cyclopropyl;hh. R⁶═CH₃ and R^(10b)═NHC(O)(CD₂)₅CD₃;ii. R⁶═CH₃ and R^(10b)═NHC(O)CD₂OCD₂CD₃;jj. R⁶═CH₃ and R^(10b)═NHC(O)CD₂N(CD₃)₂;kk. R⁶═CH₃ and R^(10b)═NHC(O)CD₂Cl;ll. R⁶═CH₃ and R^(10b)═NHC(O)OCD₂CD₃;mm. R⁶═CH₃ and R^(10b)═CD₂NHC(O)OC(CD₃)₃;nn. R⁶═CH₃ and R^(10b)═CD₂NHC(O)CD₃;oo. R⁶═CH₃ and R^(10b)═CD₂NHC(O)(CD₂)₅CD₃;pp. R⁶═CH₃ and R^(10b)═CD₂NHC(O)CD₂C(CD₃)₃;qq. R⁶═CH₃ and R^(10b)═CD₂NHC(O)-d₅-cyclopropyl;rr. R⁶═CH₃ and R^(10b)═CD₂NHC(O)CD₂N(CD₃)₂;ss. R⁶═CD₃ and R^(10b)═NHC(O)CD₂OCD₃;tt. R⁶═CD₃ and R^(10b)═NHC(O)CD₃;uu. R⁶═CD₃ and R^(10b)═NHC(O)-d₅-cyclopropyl;vv. R⁶═CD₃ and R^(10b)═NHC(O)(CD₂)₅CD₃;ww. R⁶═CD₃ and R^(10b)═NHC(O)CD₂OCD₂CD₃;xx. R⁶═CD₃ and R^(10b)═NHC(O)CD₂N(CD₃)₂;yy. R⁶═CD₃ and R^(10b)═NHC(O)CD₂Cl;zz. R⁶═CD₃ and R^(10b)═NHC(O)OCD₂CD₃;aaa. R⁶═CD₃ and R^(10b)═CD₂NHC(O)OC(CD₃)₃;bbb. R⁶═CD₃ and R^(10b)═CD₂NHC(O)CD₃;ccc. R⁶═CD₃ and R^(10b)═CD₂NHC(O)(CD₂)₅CD₃;ddd. R⁶═CD₃ and R^(10b)═CD₂NHC(O)CD₂C(CD₃)₃;eee. R⁶═CD₃ and R^(10b)═CD₂NHC(O)-d₅-cyclopropyl; and,fff. R⁶═CD₃ and R^(10b)═CD₂NHC(O)CD₂N(CD₃)₂;

and pharmaceutically acceptable salts and solvates thereof, wherein:

Z is H or D, provided that the abundance of deuterium in Z is at least30%;

R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ are independently selected from H andD; and wherein the compound of formulae IIIa or IIIb has an enantiomericexcess, with respect to the C—Z carbon, of at least 5%.

In another aspect, the present invention provides deuterium-enrichedcompounds selected from:

wherein:a. R^(d′)═C(O)CH₂OCH₃;b. R^(d′)═C(O)CH₃;c. R^(d′)═C(O)-cyclopropyl;d. R^(d′)═C(O)(CH₂)₅CH₃;e. R^(d′)═C(O)CH₂OCH₂CH₃;f. R^(d′)═C(O)CH₂N(CH₃)₂;g. R^(d′)═C(O)CH₂Cl;h. R^(d′)═C(O)OCH₂CH₃;i. R^(d′)═NHC(O)CH₂CH₂CH₃;j.

k.

wherein:l. R^(d′)═C(O)OC(CH₃)₃;m. R^(d′)═C(O)CH₃;n. R^(d′)═C(O)(CH₂)₅CH₃;o. R^(d′)═C(O)CH₂C(CH₃)₃;p. R^(d′)═C(O)-cyclopropyl; orq. R^(d′)═C(O)CH₂N(CH₃)₂;

and pharmaceutically acceptable salts and solvates thereof, wherein thecompound has an enantiomeric excess, with respect to the C—Z carbon, ofat least 5%.

In another aspect, the present invention provides deuterium-enrichedcompounds of formulae Ia-If, wherein R¹⁰═R^(10c) (compounds IVa-IVf)),and pharmaceutically acceptable salts and solvates thereof.

In another aspect, R^(g) is —(CH₂)_(n)-(6 to 10 membered aryl).

In another aspect, R^(g) is —C(O)(CH₂)_(n)-(6 to 10 membered aryl) or—C(O)(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the aryl orheteroaryl is optionally substituted as described above.

In another aspect, R^(g) is —C(O)(CH₂)_(n)NHR^(h), wherein R^(h) is 6 to10 membered aryl optionally substituted as described above.

In another aspect, R^(g) is —C(O)(CH₂)_(n)O(CH₂)_(n)-(6 to 10 memberedaryl).

In another aspect, R^(g) is —C(O)-phenyl or —C(O)—CH₂-phenyl, whereinthe phenyl is optionally substituted with a group selected from: methyl,CF₃, and halo.

In another aspect, R^(g) is —C(O)NH-phenyl, wherein the phenyl isoptionally substituted with a group selected from methyl, CF₃, and halo.

R⁶ is hydrogen.

In another aspect, R¹⁰═R^(10c) and R⁶ is —(CH₂)_(n)OH or hydroxyl.

In another aspect, R¹⁰═R^(10c) and R⁶ is phenyl.

In another aspect, R¹⁰═R^(10c) and R⁶ is —O(C₁-C₆)alkyl optionallysubstituted with one or more halo.

In another aspect, R¹⁰═R^(10c) and R⁶ is (C₁-C₆)alkyl optionallysubstituted with one or more halo.

In another aspect, R¹⁰═R^(10c) and R⁶ is methyl.

In another aspect, the present invention provides deuterium-enrichedcompounds of formulae IVa or IVb:

wherein the compound is selected from:a. R⁶═CH₃ and R^(10c)=3-Cl-phenyl-C(O)NH—;b. R⁶═CH₃ and R^(10c)=phenyl-CH₂OCH₂C(O)NH—;c. R⁶═CH₃ and R^(10c)=phenyl-CH₂C(O)NHCH₂—;d. R⁶═CH₃ and R^(10c)=pyrid-2-ylC(O)NHCH₂—;e. R⁶═CH₃ and R^(10c)=4-Cl-phenyl-CH₂C(O)NHCH₂—;f. R⁶═CH₃ and R^(10c)=4-CF₃O-phenyl-CH₂C(O)NHCH₂—;g. R⁶═CH₃ and R^(10c)=3,4-diCl-phenyl-CH₂C(O)NHCH₂—;h. R⁶═CH₃ and R^(10c)=4-F-phenyl-CH₂C(O)NHCH₂—;i. R⁶═CH₃ and R^(10c)=4-CH₃-3-F-phenyl-CH₂C(O)NHCH₂—;j. R⁶═CH₃ and R^(10c)=4-CF₃-phenyl-CH₂C(O)NHCH₂—;k. R⁶═CH₃ and R^(10c)=4-Cl-phenyl-NHC(O)NHCH₂—;l. R⁶═CH₃ and R^(10c)=4-CH₃-3-Cl-phenyl-NHC(O)NHCH₂—;m. R⁶═CH₃ and R^(10c)=3,4-diCH₃-phenyl-NHC(O)NHCH₂—;n. R⁶═CH₃ and R^(10c)=4-CH₃-phenyl-NHC(O)NHCH₂—;o. R⁶═CH₃ and R^(10c)=3-CH₃-phenyl-NHC(O)NHCH₂—;p. R⁶═CH₃ and R^(10c)=4-Cl-phenylC(O)NHCH₂—;q. R⁶═CH₃ and R^(10c)=3-F-phenylC(O)NHCH₂—;r. R⁶═CH₃ and R^(10c)=4-CF₃-phenylC(O)NHCH₂—;s. R⁶═CH₃ and R^(10c)=4-CF₃O-phenylC(O)NHCH₂—;t. R⁶═CH₃ and R^(10c)=phenylC(O)NHCH₂—;u. R⁶═CH₃ and R^(10c)=3,4-diCl-phenylC(O)NHCH₂—;v. R⁶═CH₃ and R^(10c)=3-CF₃-phenylC(O)NHCH₂—;w. R⁶═CH₃ and R^(10c)=4-CF₃S-phenylC(O)NHCH₂—;x. R⁶═CH₃ and R^(10c)=4-CH₃-3-Cl-phenylC(O)NHCH₂—;y. R⁶═CD₃ and R^(10c)=3-Cl-phenyl-C(O)NH—;z. R⁶═CD₃ and R^(10c)=phenyl-CH₂OCH₂C(O)NH—;aa. R⁶═CD₃ and R^(10c)=phenyl-CH₂C(O)NHCH₂—;bb. R⁶═CD₃ and R^(10c)=pyrid-2-ylC(O)NHCH₂—;cc. R⁶═CD₃ and R^(10c)=4-Cl-phenyl-CH₂C(O)NHCH₂—;dd. R⁶═CD₃ and R^(10c)=4-CF₃O-phenyl-CH₂C(O)NHCH₂—;ee. R⁶═CD₃ and R^(10c)=3,4-diCl-phenyl-CH₂C(O)NHCH₂—;ff. R⁶═CD₃ and R^(10c)=4-F-phenyl-CH₂C(O)NHCH₂—;gg. R⁶═CD₃ and R^(10c)=4-CH₃-3-F-phenyl-CH₂C(O)NHCH₂—;hh. R⁶═CD₃ and R^(10c)=4-CF₃-phenyl-CH₂C(O)NHCH₂—;ii. R⁶═CD₃ and R^(10c)=4-Cl-phenyl-NHC(O)NHCH₂—;jj. R⁶═CD₃ and R^(10c)=4-CH₃-3-Cl-phenyl-NHC(O)NHCH₂—;kk. R⁶═CD₃ and R^(10c)=3,4-diCH₃-phenyl-NHC(O)NHCH₂—;ll. R⁶═CD₃ and R^(10c)=4-CH₃-phenyl-NHC(O)NHCH₂—;mm. R⁶═CD₃ and R^(10c)=3-CH₃-phenyl-NHC(O)NHCH₂—;nn. R⁶═CD₃ and R^(10c)=4-Cl-phenylC(O)NHCH₂—;oo. R⁶═CD₃ and R^(10c)=3-F-phenylC(O)NHCH₂—;pp. R⁶═CD₃ and R^(10c)=4-CF₃-phenylC(O)NHCH₂—;qq. R⁶═CD₃ and R^(10c)=4-CF₃O-phenylC(O)NHCH₂—;rr. R⁶═CD₃ and R^(10c)=phenylC(O)NHCH₂—;ss. R⁶═CD₃ and R^(10c)=3,4-diCl-phenylC(O)NHCH₂—;tt. R⁶═CD₃ and R^(10c)=3-CF₃-phenylC(O)NHCH₂—;uu. R⁶═CD₃ and R^(10c)=4-CF₃S-phenylC(O)NHCH₂—;vv. R⁶═CD₃ and R^(10c)=4-CH₃-3-Cl-phenylC(O)NHCH₂—;ww. R⁶═CH₃ and R^(10c)=phenyl-CD₂OCD₂C(O)NH—;xx. R⁶═CH₃ and R^(10c)=phenyl-CD₂C(O)NHCD₂-;yy. R⁶═CH₃ and R^(10c)=pyrid-2-ylC(O)NHCD₂-;zz. R⁶═CH₃ and R^(10c)=4-Cl-phenyl-CD₂C(O)NHCD₂-;aaa. R⁶═CH₃ and R^(10c)=4-CF₃O-phenyl-CD₂C(O)NHCD₂-;bbb. R⁶═CH₃ and R^(10c)=3,4-diCl-phenyl-CD₂C(O)NHCD₂-;ccc. R⁶═CH₃ and R^(10c)=4-F-phenyl-CD₂C(O)NHCD₂-;ddd. R⁶═CH₃ and R^(10c)=4-CD₃-3-F-phenyl-CD₂C(O)NHCD₂-;eee. R⁶═CH₃ and R^(10c)=4-CF₃-phenyl-CD₂C(O)NHCD₂-;fff. R⁶═CH₃ and R^(10c)=4-Cl-phenyl-NHC(O)NHCD₂-;ggg. R⁶═CH₃ and R^(10c)=4-CD₃-3-Cl-phenyl-NHC(O)NHCD₂-;hhh. R⁶═CH₃ and R^(10c)=3,4-diCD₃-phenyl-NHC(O)NHCD₂-;iii. R⁶═CH₃ and R^(10c)=4-CD₃-phenyl-NHC(O)NHCD₂-;jjj. R⁶═CH₃ and R^(10c)=3-CD₃-phenyl-NHC(O)NHCD₂-;kkk. R⁶═CH₃ and R^(10c)=4-Cl-phenylC(O)NHCD₂-;lll. R⁶═CH₃ and R^(10c)=3-F-phenylC(O)NHCD₂-;mmm. R⁶═CH₃ and R^(10c)=4-CF₃-phenylC(O)NHCD₂-;nnn. R⁶═CH₃ and R^(10c)=4-CF₃O-phenylC(O)NHCD₂-;ooo. R⁶═CH₃ and R^(10c)=phenylC(O)NHCD₂-;ppp. R⁶═CH₃ and R^(10c)=3,4-diCl-phenylC(O)NHCD₂-;qqq. R⁶═CH₃ and R^(10c)=3-CF₃-phenylC(O)NHCD₂-;rrr. R⁶═CH₃ and R^(10c)=4-CF₃S-phenylC(O)NHCD₂-;sss. R⁶═CH₃ and R^(10c)=4-CD₃-3-Cl-phenylC(O)NHCD₂-;ttt. R⁶═CD₃ and R^(10c)=phenyl-CD₂OCD₂C(O)NH—;uuu. R⁶═CD₃ and R^(10c)=phenyl-CD₂C(O)NHCD₂-;vvv. R⁶═CD₃ and R^(10c)=pyrid-2-ylC(O)NHCD₂-;www. R⁶═CD₃ and R^(10c)=4-Cl-phenyl-CD₂C(O)NHCD₂-;xxx. R⁶═CD₃ and R^(10c)=4-CF₃O-phenyl-CD₂C(O)NHCD₂-;yyy. R⁶═CD₃ and R^(10c)=3,4-diCl-phenyl-CD₂C(O)NHCD₂-;zzz. R⁶═CD₃ and R^(10c)=4-F-phenyl-CD₂C(O)NHCD₂-;aaaa. R⁶═CD₃ and R^(10c)=4-CD₃-3-F-phenyl-CD₂C(O)NHCD₂-;bbbb. R⁶═CD₃ and R^(10c)=4-CF₃-phenyl-CD₂C(O)NHCD₂-;cccc. R⁶═CD₃ and R^(10c)=4-Cl-phenyl-NHC(O)NHCD₂-;dddd. R⁶═CD₃ and R^(10c)=4-CD₃-3-Cl-phenyl-NHC(O)NHCD₂-;eeee. R⁶═CD₃ and R^(10c)=3,4-diCD₃-phenyl-NHC(O)NHCD₂-;ffff. R⁶═CD₃ and R^(10c)=4-CD₃-phenyl-NHC(O)NHCD₂-;gggg. R⁶═CD₃ and R^(10c)=3-CD₃-phenyl-NHC(O)NHCD₂-;hhhh. R⁶═CD₃ and R^(10c)=4-Cl-phenylC(O)NHCD₂-;iiii. R⁶═CD₃ and R^(10c)=3-F-phenylC(O)NHCD₂-;jjjj. R⁶═CD₃ and R^(10c)=4-CF₃-phenylC(O)NHCD₂-;kkkk. R⁶═CD₃ and R^(10c)=4-CF₃O-phenylC(O)NHCD₂-;llll. R⁶═CD₃ and R^(10c)=phenylC(O)NHCD₂-;mmmm. R⁶═CD₃ and R^(10c)=3,4-diCl-phenylC(O)NHCD₂-;nnnn. R⁶═CD₃ and R^(10c)=3-CF₃-phenylC(O)NHCD₂-;oooo. R⁶═CD₃ and R^(10c)=4-CF₃S-phenylC(O)NHCD₂-; and,pppp. R⁶═CD₃ and R^(10c)=4-CD₃-3-Cl-phenylC(O)NHCD₂-;

and pharmaceutically acceptable salts and solvates thereof, wherein:

Z is H or D, provided that the abundance of deuterium in Z is at least30%:

R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ are independently selected from H andD; and wherein the compound of formulae IVa or IVb has an enantiomericexcess, with respect to the C—Z carbon, of at least 5%.

In another aspect, the present invention provides deuterium-enrichedcompounds selected from:

wherein:a. R^(g′)=3-Cl-phenyl;b. R^(g′)=phenyl-CH₂OCH₂—;

wherein:c. R^(g′)=phenyl-CH₂—;d. R^(g′)=pyrid-2-yl-;e. R^(g′)=4-Cl-phenyl-CH₂—;f. R^(g′)=4-CF₃O-phenyl-CH₂—;g. R^(g′)=3,4-diCl-phenyl-CH₂—;h. R^(g′)=4-F-phenyl-CH₂—;i. R^(g′)=4-CH₃-3-F-phenyl-CH₂—;j. R^(g′)=4-CF₃-phenyl-CH₂—;k. R^(g′)=4-Cl-phenyl-NH—;l. R^(g′)=4-CH₃-3-Cl-phenyl-NH—;m. R^(g′)=3,4-diCH₃-phenyl-NH—;n. R^(g′)=4-CH₃-phenyl-NH—;o. R^(g′)=3-CH₃-phenyl-NH—;p. R^(g′)=4-Cl-phenyl-;q. R^(g′)=3-F-phenyl-;r. R^(g′)=4-CF₃-phenyl-;s. R^(g′)=4-CF₃O-phenyl-;t. R^(g′)=phenyl-;u. R^(g′)=3,4-diCl-phenyl-;v. R^(g′)=3-CF₃-phenyl-;w. R^(g′)=4-CF₃S-phenyl-; andx. R^(g′)=4-CH₃-3-Cl-phenyl-;

and pharmaceutically acceptable salts and solvates thereof, wherein thecompound has an enantiomeric excess, with respect to the C—Z carbon, ofat least 5%.

In another aspect, the present invention provides deuterium-enrichedcompounds selected from:

wherein.

a. R⁶═H;

b. R⁶═OH;

c. R⁶═CH₂CH₃ where one or more H in R⁶ are optionally replaced with D;

d. R⁶═CH₂CH₂CH₃ where one or more H in R⁶ are optionally replaced withD;

e. R⁶═CF₃;

f. R⁶=phenyl where one or more H in R⁶ are optionally replaced with D;

g. R⁶═CH₃ where one or more H in R⁶ are optionally replaced with D;

wherein:

h. R^(10a)═OCH₃ where one or more H in R^(10a) are optionally replacedwith D;

i. R^(10a)═F;

j. R^(10a)═Cl;

k. R^(10a)═CF₃; and,

l.

-   -   and pharmaceutically acceptable salts and solvates thereof,        wherein the compound has an enantiomeric excess, with respect to        the C—Z carbon, of at least 5%.

In another aspect, the present invention provides a deuterium-enrichedcompound selected from:

wherein:

-   -   a. R^(d′)═C(O)CH₂OCH₃;    -   b. R^(d′)═C(O)CH₃;    -   c. R^(d′)═C(O)-cyclopropyl;    -   d. R^(d′)═C(O)(CH₂)₅CH₃;    -   e. R^(d′)═C(O)CH₂OCH₂CH₃;    -   f. R^(d′)═C(O)CH₂N(CH₃)₂;    -   g. R^(d′)═C(O)CH₂Cl;    -   h. R^(d′)═C(O)OCH₂CH₃;    -   i. R^(d′)═NHC(O)CH₂CH₂CH₃; wherein for each of the foregoing        R^(d′) one or more H is optionally replaced with D;    -   j.

-   -   -   wherein:

    -   k. R^(d′)═C(O)OC(CH₃)₃;

    -   l. R^(d′)═C(O)CH₃;

    -   m. R^(d′)═C(O)(CH₂)₅CH₃;

    -   n. R^(d′)═C(O)CH₂C(CH₃)₃;

    -   o. R^(d′)═C(O)-cyclopropyl; and

    -   p. R^(d′)═C(O)CH₂N(CH₃)₂;        and pharmaceutically acceptable salts and solvates thereof,        wherein the compound has an enantiomeric excess, with respect to        the C—Z carbon, of at least 5%.

In another aspect, the present invention provides a deuterium-enrichedcompound selected from:

wherein:

-   -   a. R^(g′)=3-Cl-phenyl;    -   b. R^(g′)=phenyl-CH₂OCH₂—;

-   -   -   wherein:

    -   c. R^(g′)=phenyl-CH₂—;

    -   d. R^(g′)=pyrid-2-yl-;

    -   e. R^(g′)=4-Cl-phenyl-CH₂—;

    -   f. R^(g′)=4-CF₃O-phenyl-CH₂—;

    -   g. R^(g′)=3,4-diCl-phenyl-CH₂—;

    -   h. R^(g′)=4-F-phenyl-CH₂—;

    -   i. R^(g′)=4-CH₃-3-F-phenyl-CH₂—;

    -   j. R^(g′)=4-CF₃-phenyl-CH₂—;

    -   k. R^(g′)=4-Cl-phenyl-NH—;

    -   l. R^(g′)=4-CH₃-3-Cl-phenyl-NH—;

    -   m. R^(g′)=3,4-diCH₃-phenyl-NH—;

    -   n. R^(g′)=4-CH₃-phenyl-NH—;

    -   o. R^(g′)=3-CH₃-phenyl-NH—;

    -   p. R^(g′)=4-Cl-phenyl-;

    -   q. R^(g′)=3-F-phenyl-;

    -   r. R^(g′)=4-CF₃-phenyl-;

    -   s. R^(g′)=4-CF₃O-phenyl-;

    -   t. R^(g′)=phenyl-;

    -   u. R^(g′)=3,4-diCl-phenyl-;

    -   v. R^(g′)=3-CF₃-phenyl-;

    -   w. R^(g′)=4-CF₃S-phenyl-; and

    -   x. R^(g′)=4-CH₃-3-Cl-phenyl-; wherein for each of the foregoing        R^(g′) one or more H is optionally replaced with D;        -   and pharmaceutically acceptable salts and solvates thereof,            wherein the compound has an enantiomeric excess, with            respect to the C—Z carbon, of at least 5%.

Additional exemplary compounds are provided in Tables 1-15 below wherevariable Z is H or D, provided that the abundance of deuterium in Z isat least 30%.

Table 1 provides compounds that are representative examples of thepresent invention wherein the compound is of Formula I and thenon-specified groups are as defined above for Formula I and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 1

Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ =H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵ = D 5R²-R⁵ = D 6 R⁷-R⁹ = D

Table 2 provides compounds that are representative examples of thepresent invention wherein the compound is of Formula Ia and thenon-specified groups are as defined above for Formula Ia and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 2 Compound No. Variable Definitioin 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸,and R⁹ = H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵= D 5 R²-R⁵ = D 6 R⁷-R⁹ = D

Table 3 provides compounds that are representative examples of thepresent invention wherein the compound is of Formula Ib and thenon-specified groups are as defined above for Formula Ib and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 3 Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸,and R⁹ = H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵= D 5 R²-R⁵ = D 6 R⁷-R⁹ = D

Table 4 provides compounds that are representative examples of thepresent invention wherein the compound is of Formula IIa and thenon-specified groups are as defined above for Formula IIa and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 4 Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸,and R⁹ = H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵= D 5 R²-R⁵ = D 6 R⁷-R⁹ = D

Table 5 provides compounds that are representative examples of thepresent invention wherein the compound is of Formula IIb and thenon-specified groups are as defined above for Formula IIb and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 5 Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸,and R⁹ = H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵= D 5 R²-R⁵ = D 6 R⁷-R⁹ = D

Table 6 provides compounds that are representative examples of thepresent invention wherein the compound is of Formula IIIa and thenon-specified groups are as defined above for Formula IIIa and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 6 Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸,and R⁹ = H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵= D 5 R²-R⁵ = D 6 R⁷-R⁹ = D

Table 7 provides compounds that are representative examples of thepresent invention wherein the compound is of Formula IIIb and thenon-specified groups are as defined above for Formula IIIb and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 7 Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸,and R⁹ = H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵= D 5 R²-R⁵ = D 6 R⁷-R⁹ = D

Table 8 provides compounds that are representative examples of thepresent invention wherein the compound is of Formula IVa and thenon-specified groups are as defined above for Formula IVa and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

Table 8

TABLE 8 Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸,and R⁹ = H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵= D 5 R²-R⁵ = D 6 R⁷-R⁹ = D

Table 9 provides compounds that are representative examples of thepresent invention wherein the compound is of Formula IVb and thenon-specified groups are as defined above for Formula IVb and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 9 Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸,and R⁹ = H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵= D 5 R²-R⁵ = D 6 R⁷-R⁹ = D

Table 10 provides compounds that are representative examples of thepresent invention wherein the compounds are of the formulae below andthe non-specified groups are as defined above for Formula I and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 10

Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ =H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵ = D 5R²-R⁵ = D 6 R⁷-R⁹ = D

Table 11 provides compounds that are representative examples of thepresent invention wherein the compounds are of the formulae below andthe non-specified groups are as defined above for Formula I and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 11

Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ =H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵ = D 5R²-R⁵ = D 6 R⁷-R⁹ = D

Table 12 provides compounds that are representative examples of thepresent invention wherein the compounds are of the formulae below andthe non-specified groups are as defined above for Formula I and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 12

Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ =H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵ = D 5R²-R⁵ = D 6 R⁷-R⁹ = D

Table 13 provides compounds that are representative examples of thepresent invention wherein the compounds are of the formulae below andthe non-specified groups are as defined above for Formula I and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 13

Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ =H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵ = D 5R²-R⁵ = D 6 R⁷-R⁹ = D

Table 14 provides compounds that are representative examples of thepresent invention wherein the compounds are of the formulae below andthe non-specified groups are as defined above for Formula I and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 14

Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ =H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵ = D 5R²-R⁵ = D 6 R⁷-R⁹ = D

Table 15 provides compounds that are representative examples of thepresent invention wherein the compounds are of the formulae below andthe non-specified groups are as defined above for Formula I and thecompounds have an enantiomeric excess, with respect to the C—Z carbon,of at least 5%.

TABLE 15

Compound No. Variable Definition 1 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ =H 2 R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ = D 3 R²-R³ = D 4 R⁴-R⁵ = D 5R²-R⁵ = D 6 R⁷-R⁹ = D

Another aspect of the invention provides a compound recited above wherea hydrogen atom present in any substituent is optionally replaced by D.

The present invention is based on stabilizing3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dionesvia deuteration at the 3-position. The C-D bond at the 3-position isstronger than the naturally occurring C—H bond. The 3-deuterium isexpected to slow the racemization of the stereogenic center at the3-position.

With hydrogen atoms being present in formulae I-IVf, the3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dionesof the present invention can be enriched beyond the 3-position. Forexample, in formula I replacing one of R¹-R⁵, R⁶-R⁹ with a deuteriumwould result in a ˜11% enrichment (9 starting hydrogens, 1/9×100=˜11%).Thus examples of additional enrichment of the 3-deutero-compounds offormula I include, but are not limited to, ˜22% (2 additionaldeuteriums), ˜33%, ˜44%, ˜55%, ˜66%, ˜77%, ˜88%, and ˜100% enrichment.In order to achieve additional enrichment less than about 11%, onlypartial deuteration of one site is required.

For other compounds of the present invention, enrichment beyond the3-position includes the presence of at least one additional deuterium.For example, enrichment can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, etc., up to the total number of hydrogen atoms present and dependingon the number of hydrogens present.

The invention also relates to isolated or purified3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-diones.The isolated or purified3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dionesis a group of molecules (i.e., an isolated compound) whose deuteriumlevels are above the naturally occurring levels. The isolated orpurified3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dionescan be obtained by techniques known to those of skill in the art.

Isolated means that the non-naturally occurring3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dionesis purified (e.g., from the reaction solution in which it was prepared).Examples of the purity of the isolated3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-diones(could be more than one type of compound) include, but are not limitedto, at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, to 100%with respect to non-deuterium-enriched3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dionecomponents being present.

The invention also relates to mixture of compounds, which means thatmore than one type of deuterated compound is being claimed.

In another aspect, the present invention provides compositionscomprising compounds of the present invention. The compositions requirethe presence of a compound of the present invention that is greater thanits natural abundance. For example, the compositions of the presentinvention can comprise (a) a pg of a compound of the present invention;(b) from 1-10 μg; (c) a mg; (d) from 1-10 mg; (e) a gram; (f) from 1-10grams; (g) from 1-100 grams; and, (h) a kg.

In another aspect, the invention provides an amount of a novel compoundof the present invention. Examples of amounts include, but are notlimited to (a) at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3,0.4, 0.5, to 1 mole, (b) at least 0.1 moles, and (c) at least 1 mole ofthe compound. The present amounts also cover lab-scale (e.g., gram scaleincluding 1, 2, 3, 4, 5 g, etc.), kilo-lab scale (e.g., kilogram scaleincluding 1, 2, 3, 4, 5 kg, etc.), and industrial or commercial scale(e.g., multi-kilogram or above scale including 100, 200, 300, 400, 500kg, etc.) quantities as these will be more useful in the actualmanufacture of a pharmaceutical.

Industrial/commercial scale refers to the amount of product that wouldbe produced in a batch that was designed for clinical testing,formulation, sale/distribution to the public, etc.

In another aspect, the invention provides novel pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a deuterium-enriched compound of theinvention.

In another aspect, the invention provides novel pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and adeuterium-enriched compound of the invention.

II. Therapeutic Applications

The invention provides methods of using deuterium-enriched compoundsdescribed herein to treat medical disorders. The deuterium-enrichedcompound can be, for example, a compound of Formula I, Formula I-A, orone of the other deuterium-enriched compounds described in Section Iabove. Various aspects of the invention pertaining to treating medicaldisorders is described below.

One aspect of the invention provides methods of treating, preventing,and/or managing various diseases or disorders using a compound providedherein, or a pharmaceutically acceptable salt, solvate (e.g., hydrate),or stereoisomer thereof. Without being limited by a particular theory,compounds provided herein are expected to control angiogenesis orinhibit the production of certain cytokines including, but not limitedto, TNF-α, IL-1β, IL-12, IL-18, GM-CSF, and/or IL-6. Without beinglimited by a particular theory, compounds provided herein may stimulatethe production of certain other cytokines including IL-10, and also actas a costimulatory signal for T cell activation, resulting in increasedproduction of cytokines such as, but are limited to, IFN-γ. In addition,compounds provided herein may enhance the effects of natural killer (NK)cells and antibody-mediated cellular cytotoxicity (ADCC). Further,compounds provided herein may be immunomodulatory and/or cytotoxic, andthus, may be useful as chemotherapeutic agents. Consequently, withoutbeing limited by a particular theory, some or all of suchcharacteristics possessed by the compounds provided herein may renderthem useful in treating, managing, and/or preventing various diseases ordisorders.

In another aspect, the invention provides for the use of an amount of adeuterium-enriched compound of the invention for the manufacture of amedicament (e.g., for treating, preventing, and/or managing angiogenesisand/or a cytokine related disorder). Yet another aspect of the inventionprovides a deuterium-enriched compound of the invention as describedabove for use in therapy.

Exemplary diseases or disorders include, but are not limited to, cancer,disorders associated with angiogenesis, pain including, but are notlimited to, Complex Regional Pain Syndrome (“CRPS”), MacularDegeneration (“MD”) and related syndromes, skin diseases, pulmonarydisorders, asbestos-related disorders, parasitic diseases,immunodeficiency disorders, CNS disorders, CNS injury, atherosclerosisand related disorders, dysfunctional sleep and related disorders,hemoglobinopathy and related disorders (e.g., anemia), TNF-α relateddisorders, and other various diseases and disorders.

Examples of cancer and precancerous conditions include, but are notlimited to, those described in U.S. Pat. Nos. 6,281,230 and 5,635,517 toMuller et al., in various U.S. patent publications to Zeldis, includingpublication nos. 2004/0220144A1, published Nov. 4, 2004 (Treatment ofMyelodysplastic Syndrome); 2004/0029832A1, published Feb. 12, 2004(Treatment of Various Types of Cancer); and 2004/0087546, published May6, 2004 (Treatment of Myeloproliferative Diseases). Examples alsoinclude those described in WO 2004/103274, published Dec. 2, 2004. Allof these references are incorporated herein in their entireties byreference.

Specific examples of cancer include, but are not limited to, cancers ofthe skin, such as melanoma; lymph node; breast; cervix; uterus;gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth;brain; head and neck; throat; testes; kidney; pancreas; bone; spleen;liver; bladder; larynx; nasal passages; and AIDS-related cancers. Thecompounds are also useful for treating cancers of the blood and bonemarrow, such as multiple myeloma and acute and chronic leukemias, forexample, lymphoblastic, myelogenous, lymphocytic, and myelocyticleukemias. The compounds provided herein can be used for treating,preventing or managing either primary or metastatic tumors.

Other specific cancers include, but are not limited to, advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karyotype acute myeloblasticleukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-celllymphoma, diffuse large B-cell lymphoma, low grade follicular lymphoma,metastatic melanoma (localized melanoma, including, but not limited to,ocular melanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressiva, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unresectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen-dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another aspect, the cancer isrefractory or resistant to chemotherapy or radiation.

Accordingly, in certain embodiments, the cancer is an advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastase, glioblastoma multiforms, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant giolma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastsleukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Celllymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, lowgrade follicular lymphoma, malignant melanoma, malignant mesothelioma,malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma,papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma,scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis,leiomyosarcoma, fibrodysplasia ossificans progressive, hormonerefractory prostate cancer, resected high-risk soft tissue sarcoma,unresceetable hepatocellular carcinoma, Waldenstrom's macroglobulinemia,smoldering myeloma, indolent myeloma, fallopian tube cancer, androgenindependent prostate cancer, androgen dependent stage IV non-metastaticprostate cancer, hormone-insensitive prostate cancer,chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma,follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.In certain other embodiments, the cancer is a cancer of the bladder,bone, blood, brain, breast, cervix, chest, colon, endrometrium,esophagus, eye, head, kidney, liver, lymph node, lung, mouth, neck,ovary, pancreas, prostate, rectum, stomach, testis, throat, or uterus.

In certain embodiments, the cancer is a solid tumor or a blood borntumor. The solid tumor and/or blood borne tumor may be metastatic and/ordrug resistant. In certain embodiments, the cancer is myeloma orlymphoma. In certain embodiments, the solid tumor is a hepatocellularcarcinoma, glioblastoma, prostate cancer, colorectal cancer, ovariancancer, or renal cancer.

In certain embodiments, the cancer is a non-Hodgkin's lymphoma that is adiffuse large B-cell lymphoma (such as characterized as being anactivated B-cell phenotype). In yet other embodiments, the cancer is anon-Hodgkin's lymphoma that is a diffuse large B-cell lymphomacharacterized by the expression of one or more biomarkers overexpressedin RIVA, U2932, TMD8, or OCI-Lyl O cell lines.

In certain embodiments, the cancer is relapsed or refractory.

In another aspect, provided herein are methods of treating, preventingor managing various forms of leukemias such as chronic lymphocyticleukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia and acute myeloblastic leukemia, includingleukemias that are relapsed, refractory or resistant, as disclosed inU.S. publication no. 2006/0030594, published Feb. 9, 2006, which isincorporated in its entirety by reference.

The term “leukemia” refers to malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another aspect, provided herein are methods of treating, preventingor managing various types of lymphomas, including Non-Hodgkin's lymphoma(NHL). The term “lymphoma” refers to a heterogenous group of neoplasmsarising in the reticuloendothelial and lymphatic systems. “NHL” refersto malignant monoclonal proliferation of lymphoid cells in sites of theimmune system, including lymph nodes, bone marrow, spleen, liver andgastrointestinal tract. Examples of NHL include, but are not limited to,mantle cell lymphoma (MCL), lymphocytic lymphoma of intermediatedifferentiation, intermediate lymphocytic lymphoma (ILL), diffuse poorlydifferentiated lymphocytic lymphoma (PDL), centrocytic lymphoma, diffusesmall-cleaved cell lymphoma (DSCCL), follicular lymphoma, and any typeof the mantle cell lymphomas that can be seen under the microscope(nodular, diffuse, blastic and mantle zone lymphoma).

Additional exemplary diseases and disorders associated with, orcharacterized by, undesired angiogenesis include, but are not limitedto, inflammatory diseases, autoimmune diseases, viral diseases, geneticdiseases, allergic diseases, bacterial diseases, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,and rubeosis iridis (neovascularization of the angle of the eye).Specific examples of the diseases and disorders associated with, orcharacterized by, undesired angiogenesis include, but are not limitedto, arthritis, endometriosis, Crohn's disease, heart failure, advancedheart failure, renal impairment, endotoxemia, toxic shock syndrome,osteoarthritis, retrovirus replication, wasting, meningitis,silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorder,malignancy-associated hypercalcemia, stroke, circulatory shock,periodontitis, gingivitis, macrocytic anemia, refractory anemia, and5q-deletion syndrome.

In certain embodiments, the disorder to be treated is an immune diseaseor an inflammatory disease. In certain other embodiments, the disorderto be treated is systemic lupus erythematosus, scleroderma, Sjogrensyndrome, ANCA-induced vasculitis, anti-phospholipid syndrome, ormyasthenia gravis. The scleroderma may be localized, systemic, limited,or diffuse scleroderma. In certain embodiments, the systemic sclerodermacomprises CREST syndrome (Calcinosis, Raynaud's syndrome, esophagaealdysfunction or dysmotility, sclerodactyly, telangiectasia). Sclerodermais also known as systemic sclerosis or progressive systemic sclerosis.In certain embodiments, systemic sclerosis comprises scleroderma lungdisease, scleroderma renal crisis, cardiac manifestations, muscularweakness (including fatigue or limited CREST), gastrointestinaldysmotility and spasm, and abnormalities in the central, peripheral andautonomic nervous system (including carpal tunnel syndrome followed bytrigeminal neuralgia).

It also includes general disability, including depression, and impact onquality of life. In certain embodiments, limited scleroderma is limitedto the hands, the face, neck, or combinations thereof. In certainembodiments, diffuse scleroderma comprises skin tightening and alsooccurs above the wrists (or elbows). In yet other embodiments, diffusesystemic sclerosis is sine scleroderma, comprising internal organfibrosis, but no skin tightening; or familial progressive systemicsclerosis.

In certain embodiments, the disorder to be treated is Raynaud's diseaseor syndrome.

Another aspect of the invention provides a method for reducing,inhibiting or preventing a symptom of systemic lupus erythematosus byadministering to a patient suffering from systemic lupus erythematosus adeuterium-enriched compound described herein, wherein the symptom is oneor more of joint pain, joint swelling, arthritis, chest pain when takinga deep breath, fatigue, fever with no other cause, general discomfort,uneasiness, hair loss, mouth sores, swollen lymph nodes, sensitivity tosunlight, skin rash, headaches, numbness, tingling, seizures, visionproblems, personality changes, abdominal pain, nausea, vomiting,abnormal heart rhythms, coughing up blood, difficulty breathing, patchyskin color, or Raynaud's phenomenon.

Another aspect of the invention provides a method for reducing,inhibiting or preventing a symptom of scleroderma by administering to apatient suffering from scleroderma a deuterium-enriched compounddescribed herein, wherein the symptom is one or more of (i) gradualhardening, thickening, and tightening of the skin; (ii) skindiscoloration; (iii) numbness of extremities; (iv) shiny skin; (v) smallwhite lumps under the surface of the skin that erupt into a chalky whitefluid; (vi) Raynaud's esophagaeal dysfunction; (vii) telangiectasia;(viii) pain and/or stiffness of the joints; (ix) swelling of the handsand feet; (x) itching of the skin; (xi) stiffening and curling of thefingers; (xii) ulcers on the outside of certain joints, such as knucklesand elbows; (xiii) digestive problems, such as heartburn, difficulty inswallowing, diarrhea, irritable bowel, and constipation; (xiv) fatigueand weakness; (xv) shortness of breath; (xvi) arthritis; (xvii) hairloss; (xviii) internal organ problems; (xix) digital ulcers; and (xx)digital auto-amputation.

Another aspect of the invention provides a method for improving themodified Rodnan skin score, reducing or improving the skin thickness,reducing or improving skin induration, improving the pulmonary function,improving the dermatology quality of life index, improving the carbonmonoxide diffusing capacity, improving the Mahler Dyspnea index,improving the Saint George's Respiratory Questionnaire score, improvingthe UCLA scleroderma clinical trial consortium gastrointestinal tractscore, improving flow-mediated dilatation, or improving or increasingthe six minute walk distance of a patient having scleroderma, comprisingadministering to the patient an effective amount of a deuterium-enrichedcompound described herein.

Another aspect of the invention provides a method for modulatingactivity of a cell selected from the group consisting of a B cell and aT cell, comprising contacting the cell with an effective amount of adeuterium-enriched compound described herein to modulate the activity ofthe cell.

Another aspect of the invention provides a method for treating animmune-related disorder or a disorder selected from the group consistingof Sjogren syndrome, ANCA-induced vasculitis, anti-phospholipidsyndrome, myasthenia gravis, Addison's disease, alopecia areata,ankylosing spondylitis, antiphospholipid antibody syndrome,antiphospholipid syndrome (primary or secondary), asthma, autoimmunegastritis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmuneinner ear disease, autoimmune lymphoproliferative disease, autoimmunethrombocytopenic purpura, Balo disease, Behcet's disease, bullouspemphigoid, cardiomyopathy, celiac disease, Chagas disease, chronicinflammatory demyelinating polyneuropathy, cicatrical pemphigoid (e.g.,mucous membrane pemphigoid), cold agglutinin disease, Degos disease,dermatitis hepatiformis, essential mixed cryoglobulinemia, Goodpasture'ssyndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto'sthyroiditis (Hashimoto's disease; autoimmune thyroiditis), idiopathicpulmonary fibrosis, idiopathic thrombocytopenia purpura, IgAnephropathy, juvenile arthritis, lichen planus, Meniere disease, mixedconnective tissue disease, morphea, narcolepsy, neuromyotonia, pediatricautoimmune neuropsychiatric disorders (P AND As), pemphigus vulgaris,pernicious anemia, polyarteritis nodosa, polychondritis, polymyalgiarheumatica, primary agammaglobulinemia, primary biliary cirrhosis,Raynaud's disease (Raynaud's phenomenon), Reiter's syndrome, relapsingpolychondritis, rheumatic fever, Sjogren's syndrome, stiff-personsyndrome (Moersch-Woltmann syndrome), Takayasu's arteritis, temporalarteritis (giant cell arteritis), uveitis, vasculitis (e.g., vasculitisnot associated with lupus erythematosus), vitiligo, and Wegener'sgranulomatosis. The method comprises administering to a patient in needthereof a therapeutically effective amount of a deuterium-enrichedcompound described herein to treat the disorder.

Another aspect of the invention provides a method of treating orpreventing pain in a subject, comprising administering to a patient inneed thereof a therapeutically effective amount of a deuterium-enrichedcompound described herein. Exemplary types of pain include nociceptivepain, neuropathic pain, mixed pain of nociceptive and neuropathic pain,visceral pain, migraine, headache and post-operative pain.

Examples of nociceptive pain include, but are not limited to, painassociated with chemical or thermal burns, cuts of the skin, contusionsof the skin, osteoarthritis, rheumatoid arthritis, tendonitis, andmyofascial pain.

Examples of neuropathic pain include, but are not limited to, complexregional pain syndrome (CRPS) type I, CRPS type II, reflex sympatheticdystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy,sympathetically maintained pain syndrome, causalgia, Sudeck atrophy ofbone, algoneurodystrophy, shoulder hand syndrome, post-traumaticdystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer relatedpain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinalcord injury pain, central post-stroke pain, radiculopathy, diabeticneuropathy, post-stroke pain, luetic neuropathy, and other painfulneuropathic conditions such as those induced by drugs such asvincristine and velcade.

Complex regional pain syndrome (CRPS) and CRPS and related syndromesmean a chronic pain disorder characterized by one or more of thefollowing: pain, whether spontaneous or evoked, including allodynia(painful response to a stimulus that is not usually painful) andhyperalgesia (exaggerated response to a stimulus that is usually onlymildly painful); pain that is disproportionate to the inciting event(e.g., years of severe pain after an ankle sprain); regional pain thatis not limited to a single peripheral nerve distribution; and autonomicdysregulation (e.g., edema, alteration in blood flow and hyperhidrosis)associated with trophic skin changes (hair and nail growth abnormalitiesand cutaneous ulceration).

Further types of pain contemplated for treatment include, but are notlimited to, those described in U.S. patent publication no. 2005/0203142,published Sep. 15, 2005, which is incorporated in its entirety herein byreference.

Examples of macular degeneration (MD) and related syndromes include, butare not limited to, those described in U.S. patent publication no.2004/0091455, published May 13, 2004, which is incorporated in itsentirety herein by reference. Specific examples include, but are notlimited to, atrophic (dry) MD, exudative (wet) MD, age-relatedmaculopathy (ARM), choroidal neovascularisation (CNVM), retinal pigmentepithelium detachment (PED), and atrophy of retinal pigment epithelium(RPE).

Examples of skin diseases include, but are not limited to, thosedescribed in U.S. publication no. 2005/0214328A1, published Sep. 29,2005, which is incorporated in its entirety herein by reference.Specific examples include, but are not limited to, keratoses and relatedsymptoms, skin diseases or disorders characterized with overgrowths ofthe epidermis, acne, and wrinkles.

“Keratosis” refers to any lesion on the epidermis marked by the presenceof circumscribed overgrowths of the horny layer, including but notlimited to, actinic keratosis, seborrheic keratosis, keratoacanthoma,keratosis follicularis (Darier disease), inverted follicular keratosis,palmoplantar keratoderma (PPK, keratosis palmaris et plantaris),keratosis pilaris, and stucco keratosis. The term “actinic keratosis”also refers to senile keratosis, keratosis senilis, verruca senilis,plana senilis, solar keratosis, keratoderma or keratoma. The term“seborrheic keratosis” also refers to seborrheic wart, senile wart, orbasal cell papilloma. Keratosis is characterized by one or more of thefollowing symptoms: rough appearing, scaly, erythematous papules,plaques, spicules or nodules on exposed surfaces (e.g., face, hands,ears, neck, legs and thorax), excrescences of keratin referred to ascutaneous horns, hyperkeratosis, telangiectasias, elastosis, pigmentedlentigines, acanthosis, parakeratosis, dyskeratosis, papillomatosis,hyperpigmentation of the basal cells, cellular atypia, mitotic figures,abnormal cell-cell adhesion, dense inflammatory infiltrates and smallprevalence of squamous cell carcinomas.

Examples of skin diseases or disorders characterized with overgrowths ofthe epidermis include, but are not limited to, any conditions, diseasesor disorders marked by the presence of overgrowths of the epidermis,including but not limited to, infections associated with papillomavirus, arsenical keratosis, sign of Leser-Trelat, warty dyskeratoma(WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV),ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneousmelanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,confluent and reticulated papillomatosis (CRP), acrochordons, cutaneoushorn, Cowden disease (multiple hamartoma syndrome), dermatosis papulosanigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris,molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

Examples of pulmonary disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0239842A1, published Oct. 27,2005, which is incorporated in its entirety herein by reference.Specific examples include pulmonary hypertension and related disorders.Examples of pulmonary hypertension and related disorders include, butare not limited to: primary pulmonary hypertension (PPH); secondarypulmonary hypertension (SPH); familial PPH; sporadic PPH; precapillarypulmonary hypertension; pulmonary arterial hypertension (PAH); pulmonaryartery hypertension; idiopathic pulmonary hypertension; thromboticpulmonary arteriopathy (TPA); plexogenic pulmonary arteriopathy;functional classes I to IV pulmonary hypertension; and pulmonaryhypertension associated with, related to, or secondary to, leftventricular dysfunction, mitral valvular disease, constrictivepericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis,anomalous pulmonary venous drainage, pulmonary venoocclusive disease,collagen vascular disease, congenital heart disease, HIV virusinfection, drugs and toxins such as fenfluramine, congenital heartdisease, pulmonary venous hypertension, chronic obstructive pulmonarydisease, interstitial lung disease, sleep-disordered breathing, alveolarhypoventilation disorder, chronic exposure to high altitude, neonatallung disease, alveolar-capillary dysplasia, sickle cell disease, othercoagulation disorder, chronic thromboemboli, connective tissue disease,lupus including systemic and cutaneous lupus, schistosomiasis,sarcoidosis or pulmonary capillary hemangiomatosis.

Examples of asbestos-related disorders include, but are not limited to,those described in U.S. publication no. 2005/0100529, published May 12,2005, which is incorporated in its entirety herein by reference.Specific examples include, but are not limited to, mesothelioma,asbestosis, malignant pleural effusion, benign exudative effusion,pleural plaques, pleural calcification, diffuse pleural thickening,rounded atelectasis, fibrotic masses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, thosedescribed in U.S. publication no. 2006/0154880, published Jul. 13, 2006,which is incorporated in its entirety herein by reference. Parasiticdiseases include diseases and disorders caused by human intracellularparasites such as, but not limited to, P. falcifarium, P. ovale, P.vivax, P. malariae, L. donovari, L. infantum, L. aethiopica, L. major,L. tropica, L. mexicana, L. braziliensis, T. gondii, B. microti, B.divergens, B. coli, C. parvum, C. cayetanensis, E. histolytica, I.belli, S. mansonii, S. haematobium, Trypanosoma ssp., Toxoplasma ssp.,and O. volvulus. Other diseases and disorders caused by non-humanintracellular parasites such as, but not limited to, Babesia bovis,Babesia canis, Banesia gibsoni, Besnoitia darlingi, Cytauxzoon felis,Eimeria ssp., Hammondia ssp., and Theileria ssp., are also encompassed.Specific examples include, but are not limited to, malaria, babesiosis,trypanosomiasis, leishmaniasis, toxoplasmosis, meningoencephalitis,keratitis, amebiasis, giardiasis, cryptosporidiosis, isosporiasis,cyclosporiasis, microsporidiosis, ascariasis, trichuriasis,ancylostomiasis, strongyloidiasis, toxocariasis, trichinosis, lymphaticfilariasis, onchocerciasis, filariasis, schistosomiasis, and dermatitiscaused by animal schistosomes.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. application Ser. No. 11/289,723, filed Nov. 30,2005. Specific examples include, but are not limited to, adenosinedeaminase deficiency, antibody deficiency with normal or elevated Igs,ataxia-telangiectasia, bare lymphocyte syndrome, common variableimmunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions, IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective IgG subclass deficiency,transient hypogammaglobulinemia of infancy, Wistcott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0143344, published Jun. 30, 2005,which is incorporated in its entirety herein by reference. Specificexamples include, but are not limited to, amyotrophic lateral sclerosis,Alzheimer's disease, Parkinson's disease, Huntington's disease, multiplesclerosis, other neuroimmunological disorders such as Tourette syndrome,delirium, or disturbances in consciousness that occur over a shortperiod of time, and amnestic disorder, or discreet memory impairmentsthat occur in the absence of other central nervous system impairments.

Examples of CNS injuries and related syndromes include, but are notlimited to, those described in U.S. publication no. 2006/0122228,published Jun. 8, 2006, which is incorporated in its entirety herein byreference. Specific examples include, but are not limited to, CNSinjury/damage and related syndromes, include, but are not limited to,primary brain injury, secondary brain injury, traumatic brain injury,focal brain injury, diffuse axonal injury, head injury, concussion,post-concussion syndrome, cerebral contusion and laceration, subduralhematoma, epidermal hematoma, post-traumatic epilepsy, chronicvegetative state, complete spinal cord injury (SCI), incomplete SCI,acute SCI, subacute SCI, chronic SCI, central cord syndrome,Brown-Sequard syndrome, anterior cord syndrome, conus medullarissyndrome, cauda equina syndrome, neurogenic shock, spinal shock, alteredlevel of consciousness, headache, nausea, emesis, memory loss,dizziness, diplopia, blurred vision, emotional lability, sleepdisturbances, irritability, inability to concentrate, nervousness,behavioral impairment, cognitive deficit, and seizure.

Other disease or disorders include, but are not limited to, viral,genetic, allergic, and autoimmune diseases. Specific examples include,but are not limited to, HIV, hepatitis, adult respiratory distresssyndrome, bone resorption diseases, chronic pulmonary inflammatorydiseases, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxicshock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusioninjury, meningitis, psoriasis, fibrotic disease, cachexia, graft versushost disease, graft rejection, auto-immune disease, rheumatoidspondylitis, Crohn's disease, ulcerative colitis, inflammatory boweldisease, multiple sclerosis, systemic lupus erythrematosus, ENL inleprosy, radiation damage, cancer, asthma, or hyperoxic alveolar injury.

Examples of atherosclerosis and related conditions include, but are notlimited to, those disclosed in U.S. publication no. 2002/0054899,published May 9, 2002, which is incorporated in its entirety herein byreference. Specific examples include, but are not limited to, all formsof conditions involving atherosclerosis, including restenosis aftervascular intervention such as angioplasty, stenting, atherectomy andgrafting. All forms of vascular intervention are contemplated herein,including diseases of the cardiovascular and renal system, such as, butnot limited to, renal angioplasty, percutaneous coronary intervention(PCI), percutaneous transluminal coronary angioplasty (PTCA), carotidpercutaneous transluminal angioplasty (PTA), coronary bypass grafting,angioplasty with stent implantation, peripheral percutaneoustransluminal intervention of the iliac, femoral or popliteal arteries,and surgical intervention using impregnated artificial grafts.

The following chart provides a listing of the major systemic arteriesthat may be in need of treatment, all of which are contemplated herein:

Artery Body Areas Supplied Axillary Shoulder and axilla Brachial Upperarm Brachiocephalic Head, neck, and arm Celiac Divides into leftgastric, splenic, and hepatic arteries Common carotid Neck Common iliacDivides into external and internal iliac arteries Coronary Heart Deepfemoral Thigh Digital Fingers Dorsalis pedis Foot External carotid Neckand external head regions External iliac Femoral artery Femoral ThighGastric Stomach Hepatic Liver, gallbladder, pancreas, and duodenumInferior mesenteric Descending colon, rectum, and pelvic wall Internalcarotid Neck and internal head regions Internal iliac Rectum, urinarybladder, external genitalia, buttocks muscles, uterus and vagina Leftgastric Esophagus and stomach Middle sacral Sacrum Ovarian OvariesPalmar arch Hand Peroneal Calf Popliteal Knee Posterior tibial CalfPulmonary Lungs Radial Forearm Renal Kidney Splenic Stomach, pancreas,and spleen Subclavian Shoulder Superior mesenteric Pancreas, smallintestine, ascending and transverse colon Testicular Testes UlnarForearm

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. publication no. 2005/0222209A1,published Oct. 6, 2005, which is incorporated in its entirety herein byreference. Specific examples include, but are not limited to, snoring,sleep apnea, insomnia, narcolepsy, restless leg syndrome, sleep terrors,sleep walking, sleep eating, and dysfunctional sleep associated withchronic neurological or inflammatory conditions. Chronic neurological orinflammatory conditions, include, but are not limited to, complexregional pain syndrome (CRPS), chronic low back pain, musculoskeletalpain, arthritis, radiculopathy, pain associated with cancer,fibromyalgia, chronic fatigue syndrome, visceral pain, bladder pain,chronic pancreatitis, neuropathies (diabetic, post-herpetic, traumaticor inflammatory), and neurodegenerative disorders such as Parkinson'sdisease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS),multiple sclerosis, Huntington's disease, bradykinesia; muscle rigidity;parkinsonian tremor; parkinsonian gait; motion freezing; depression;defective long-term memory, Rubinstein-Taybi syndrome (RTS); dementia;postural instability; hypokinetic disorders; synuclein disorders;multiple system atrophies; striatonigral degeneration;olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron diseasewith parkinsonian features; Lewy body dementia; Tau pathology disorders;progressive supranuclear palsy; corticobasal degeneration;frontotemporal dementia; amyloid pathology disorders; mild cognitiveimpairment; Alzheimer's disease with parkinsonism; Wilson disease;Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3spinocerebellar ataxia; X-linked dystonia parkinsonism; prion disease;hyperkinetic disorders; chorea; ballismus; dystonia tremors; CNS traumaand myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. publication no. 2005/0143420A1,published Jun. 30, 2005, which is incorporated in its entirety herein byreference. Specific examples include, but are not limited to,hemoglobinopathy, sickle cell anemia, and any other disorders related tothe differentiation of CD34+ cells.

Examples of TNFα related disorders include, but are not limited to,those described in WO 98/03502 and WO 98/54170, both of which areincorporated herein in their entireties by reference. Specific examplesinclude, but are not limited to: endotoxemia or toxic shock syndrome;cachexia; adult respiratory distress syndrome; bone resorption diseasessuch as arthritis; hypercalcemia; graft versus host reaction; cerebralmalaria; inflammation; tumor growth; chronic pulmonary inflammatorydiseases; reperfusion injury; myocardial infarction; stroke; circulatoryshock; rheumatoid arthritis; Crohn's disease; HIV infection and AIDS;other disorders such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, psoriatic arthritis and other arthritic conditions,septic shock, sepsis, endotoxic shock, graft versus host disease,wasting, ulcerative colitis, multiple sclerosis, systemic lupuserythromatosis, ENL in leprosy, HIV, AIDS, and opportunistic infectionsin AIDS; disorders such as endotoxic shock, hemodynamic shock and sepsissyndrome, post ischemic reperfusion injury, malaria, mycobacterialinfection, meningitis, psoriasis, congestive heart failure, fibroticdisease, graft rejection, oncogenic or cancerous conditions, asthma,autoimmune disease, radiation damages, and hyperoxic alveolar injury;viral infections, such as those caused by the herpes viruses; viralconjunctivitis; or atopic dermatitis.

In other aspects, the use of compounds provided herein in variousimmunological applications, in particular, as vaccine adjuvants,particularly anticancer vaccine adjuvants, as disclosed in USpublication number 2007/0048327, which is incorporated herein in itsentirety by reference, is also encompassed. These embodiments alsorelate to the uses of compounds provided herein in combination withvaccines to treat or prevent cancer or infectious diseases, and othervarious uses of immunomodulatory compounds such as reduction ordesensitization of allergic reactions.

Additional medical disorders for treatment include those described ininternational patent application publication nos. WO 2012/125459 and WO2012/125475, each of which is hereby incorporated by reference.

Dosages

Doses of a compound provided herein, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, vary depending on factors suchas: specific indication to be treated, prevented, or managed; age andcondition of a patient; and amount of second active agent used, if any.Generally, a compound provided herein, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, may be used in an amount of fromabout 0.1 mg to about 500 mg per day, and can be adjusted in aconventional fashion (e.g., the same amount administered each day of thetreatment, prevention or management period), in cycles (e.g., one weekon, one week off), or in an amount that increases or decreases over thecourse of treatment, prevention, or management. In other embodiments,the dose can be from about 1 mg to about 300 mg, from about 0.1 mg toabout 150 mg, from about 1 mg to about 200 mg, from about 10 mg to about100 mg, from about 0.1 mg to about 50 mg, from about 1 mg to about 50mg, from about 10 mg to about 50 mg, from about 20 mg to about 30 mg, orfrom about 1 mg to about 20 mg.

Second Active Agents

A compound provided herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, can be combined with otherpharmacologically active compounds (“second active agents”) in methodsand compositions provided herein. Certain combinations may worksynergistically in the treatment of particular types of diseases ordisorders, and conditions and symptoms associated with such diseases ordisorders. A compound provided herein, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, can also work to alleviateadverse effects associated with certain second active agents, and viceversa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40); histonedeacetylase inhibitors (such as, for example, SAHA and LAQ 824);heat-shock protein-90 inhibitors (such as, for example, 17-AAG);insulin-like growth factor-1 receptor kinase inhibitors; vascularendothelial growth factor receptor kinase inhibitors (such as, forexample, PTK787); insulin growth factor receptor inhibitors;lysophosphatidic acid acyltransferase inhibitors; IkB kinase inhibitors;p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib anderlotinib HCl); HER-2 antibodies (such as, for example, trastuzumab(Herceptin®) and pertuzumab (Perjeta®)); VEGFR antibodies (such as, forexample, bevacizumab (Avastin®)); VEGFR inhibitors (such as, forexample, flk-1 specific kinase inhibitors, SU5416 and ptk787/zk222584);PI3K inhibitors (such as, for example, wortmannin); C-Met inhibitors(such as, for example, PHA-665752); monoclonal antibodies (such as, forexample, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab(Panorex®) and G250); and anti-TNF-α antibodies. Examples of smallmolecule active agents include, but are not limited to, anticanceragents and antibiotics (e.g., clarithromycin).

Specific second active compounds that can be combined with compoundsprovided herein vary depending on the specific indication to be treated,prevented or managed.

For instance, for the treatment, prevention or management of cancer,second active agents include, but are not limited to: semaxanib;cyclosporin; etanercept; doxycycline; bortezomib; acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinyispermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; iloinastat; imatinib (Gleevec®), imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lyticpeptides; maitansine; mannostatin A; marimastat; masoprocol; maspin;matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril;merbarone; ineterelin; methioninase; metoclopramide; MIF inhibitor;inifepristone; miltefosine; mirimostim; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, humanchorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wallsk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterialcell wall extract; myriaporone; N-acetyldinaline; N-substitutedbenzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;nitrullyn; oblimersen (Genasense®); O6-benzylguanine; octreotide;okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillylalcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetinA; placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginoneB1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; sizofuran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stipiamide; stromelysininhibitors; sulfinosine; superactive vasoactive intestinal peptideantagonist; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in multiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

In another aspect, examples of specific second agents according to theindications to be treated, prevented, or managed can be found in thefollowing references, all of which are incorporated herein in theirentireties: U.S. Pat. Nos. 6,281,230 and 5,635,517; U.S. publicationnos. 2004/0220144, 2004/0190609, 2004/0087546, 2005/0203142,2004/0091455, 2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880,2006/0122228, 2005/0143344, and 2006/0188475.

Examples of second active agents that may be used for the treatment,prevention and/or management of pain include, but are not limited to,conventional therapeutics used to treat or prevent pain such asantidepressants, anticonvulsants, antihypertensives, anxiolytics,calcium channel blockers, muscle relaxants, non-narcotic analgesics,opioid analgesics, anti-inflammatories, COX-2 inhibitors,immunomodulatory agents, alpha-adrenergic receptor agonists orantagonists, immunosuppressive agents, corticosteroids, hyperbaricoxygen, ketamine, other anesthetic agents, NMDA antagonists, and othertherapeutics found, for example, in the Physician's Desk Reference 2003.Specific examples include, but are not limited to, salicylic acidacetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin(Neurontin®), phenyloin (Dilantin®), carbamazepine (Tegretol®),oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate,hydromorphone, prednisone, griseofulvin, penthonium, alendronate,dyphenhydramide, guanethidine, ketorolac (Acular®), thyrocalcitonin,dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin,reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine,acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®),imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®),fluoxetine (Prozac®), sertraline (Zoloft®), naproxen, nefazodone(Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®), bupropion(Wellbutrin®), mexiletine, nifedipine, propranolol, tramadol,lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan,benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Examples of second active agents that may be used for the treatment,prevention and/or management of macular degeneration and relatedsyndromes include, but are not limited to, a steroid, a lightsensitizer, an integrin, an antioxidant, an interferon, a xanthinederivative, a growth hormone, a neutrotrophic factor, a regulator ofneovascularization, an anti-VEGF antibody, a prostaglandin, anantibiotic, a phytoestrogen, an anti-inflammatory compound or anantiangiogenesis compound, or a combination thereof. Specific examplesinclude, but are not limited to, verteporfin, purlytin, an angiostaticsteroid, rhuFab, interferon-2-alpha, pentoxifylline, tin etiopurpurin,motexafin lutetium, lucentis, lutetium,9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione,latanoprost (see U.S. Pat. No. 6,225,348), tetracycline and itsderivatives, rifamycin and its derivatives, macrolides, metronidazole(U.S. Pat. Nos. 6,218,369 and 6,015,803), genistein, genistin, 6′-O-Malgenistin, 6′-O—Ac genistin, daidzein, daidzin, 6′-O-Mal daidzin, 6′-O—Acdaidzin, glycitein, glycitin, 6′-O-Mal glycitin, biochanin A,formononetin (U.S. Pat. No. 6,001,368), triamcinolone acetomide,dexamethasone (U.S. Pat. No. 5,770,589), thalidomide, glutathione (U.S.Pat. No. 5,632,984), basic fibroblast growth factor (bFGF), transforminggrowth factor b (TGF-b), brain-derived neurotrophic factor (BDNF),plasminogen activator factor type 2 (PAI-2), EYE101 (EyetechPharmaceuticals), LY333531 (Eli Lilly), Miravant, and RETISERT implant(Bausch & Lomb). All of the references cited herein are incorporated intheir entireties by reference.

Examples of second active agents that may be used for the treatment,prevention and/or management of skin diseases include, but are notlimited to, keratolytics, retinoids, α-hydroxy acids, antibiotics,collagen, botulinum toxin, interferon, steroids, and immunomodulatoryagents. Specific examples include, but are not limited to,5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lacticacid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics,collagen, botulinum toxin, interferon, corticosteroid, transretinoicacid and collagens such as human placental collagen, animal placentalcollagen, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm,Zyplast, Resoplast, and Isolagen.

Examples of second active agents that may be used for the treatment,prevention and/or management of pulmonary hypertension and relateddisorders include, but are not limited to, anticoagulants, diuretics,cardiac glycosides, calcium-channel blockers, vasodilators, prostacyclinanalogues, endothelin antagonists, phosphodiesterase inhibitors (e.g.,PDE V inhibitors), endopeptidase inhibitors, lipid-lowering agents,thromboxane inhibitors, and other therapeutics known to reduce pulmonaryartery pressure. Specific examples include, but are not limited to,warfarin (Coumadin®), a diuretic, a cardiac glycoside, digoxin-oxygen,diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g.,prostaglandin I2 (PGI2)), epoprostenol (EPO, Floran®), treprostinil(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine,prostacyclin, tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat(Vanlev®), irbesartan (Avapro®), pravastatin (Pravachol®), digoxin,L-arginine, iloprost, betaprost, and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment,prevention and/or management of asbestos-related disorders include, butare not limited to, anthracycline, platinum, alkylating agents,oblimersen (Genasense®), cisplatinum, cyclophosphamide, temodar,carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine,carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel,vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid,palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenictrioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir,adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa,tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment,prevention and/or management of parasitic diseases include, but are notlimited to, chloroquine, quinine, quinidine, pyrimethamine,sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine,primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin,suramin, pentamidine, melarsoprol, nifurtimox, benznidazole,amphotericin B, pentavalent antimony compounds (e.g., sodiumstibogluconate), interferon gamma, itraconazole, a combination of deadpromastigotes and BCG, leucovorin, corticosteroids, sulfonamide,spiramycin, IgG (serology), trimethoprim, and sulfamethoxazole.

Examples of second active agents that may be used for the treatment,prevention and/or management of immunodeficiency disorders include, butare not limited to: antibiotics (therapeutic or prophylactic) such as,but not limited to, ampicillin, tetracycline, penicillin,cephalosporins, streptomycin, kanamycin, and erythromycin; antiviralssuch as, but not limited to, amantadine, rimantadine, acyclovir, andribavirin; immunoglobulin; plasma; immunologic enhancing drugs such as,but not limited to, levamisole and isoprinosine; biologics such as, butnot limited to, gammaglobulin, transfer factor, interleukins, andinterferons; hormones such as, but not limited to, thymic hormones; andother immunologic agents such as, but not limited to, B cell stimulators(e.g., BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growthfactors (e.g., TGF-α), antibodies (e.g., anti-CD40 and IgM),oligonucleotides containing unmethylated CpG motifs, and vaccines (e.g.,viral and tumor peptide vaccines).

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS disorders include, but are notlimited to: opioids; a dopamine agonist or antagonist, such as, but arenot limited to, Levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine,tetrabenazine, benzotropine, pargyline, fenoldopam mesylate,cabergoline, pramipexole dihydrochloride, ropinorole, amantadinehydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate,Sinemet CR, and Symmetrel; a MAO inhibitor, such as, but not limited to,iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT inhibitor,such as, but not limited to, tolcapone and entacapone; a cholinesteraseinhibitor, such as, but not limited to, physostigmine salicylate,physostigmine sulfate, physostigmine bromide, neostigmine bromide,neostigmine methylsulfate, ambenonium chloride, edrophonium chloride,tacrine, pralidoxime chloride, obidoxime chloride, trimedoxime bromide,diacetyl monoxime, pyridostigmine, and demecarium bromide; ananti-inflammatory agent, such as, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, ineloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone or betamethasone and other glucocorticoids; and anantiemetic agent, such as, but not limited to, metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS injuries and related syndromesinclude, but are not limited to, immunomodulatory agents,immunosuppressive agents, antihypertensives, anticonvulsants,fibrinolytic agents, antiplatelet agents, antipsychotics,antidepressants, benzodiazepines, buspirone, amantadine, and other knownor conventional agents used in patients with CNS injury/damage andrelated syndromes. Specific examples include, but are not limited to:steroids (e.g., glucocorticoids, such as, but not limited to,methylprednisolone, dexamethasone and betamethasone); ananti-inflammatory agent, including, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, RHo-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone; a cAMP analog including, but not limited to, db-cAMP; anagent comprising a methylphenidate drug, which comprises1-threo-methylphenidate, d-threo-methyl phenidate,dl-threo-methylphenidate, 1-erythro-methylphenidate,d-erythro-methylphenidate, dl-erythro-methylphenidate, and a mixturethereof; and a diuretic agent such as, but not limited to, mannitol,furosemide, glycerol, and urea.

Examples of second active agent that may be used for the treatment,prevention and/or management of dysfunctional sleep and relatedsyndromes include, but are not limited to, a tricyclic antidepressantagent, a selective serotonin reuptake inhibitor, an antiepileptic agent(gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam,topiramate), an antiaryhthmic agent, a sodium channel blocking agent, aselective inflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin®, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,a-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,fenoldopam mesylate, cabergoline, pramipexole dihydrochloride,ropinorole, amantadine hydrochloride, selegiline hydrochloride,carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazid,clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine salicylate, physostigmine sulfate, physostigmine bromide,neostigmine bromide, neostigmine methylsulfate, ambenonium chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxime, pyridostigmine, demecariumbromide, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, Rho-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac,flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam,pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine,aminopyrine, apazone, zileuton, aurothioglucose, gold sodium thiomalate,auranofin, methotrexate, colchicine, allopurinol, probenecid,sulfinpyrazone, benzbromarone, betamethasone and other glucocorticoids,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, pipamazine, scopolamine, sulpiride,tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron,and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of hemoglobinopathy and related disordersinclude, but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-2 (“r1L2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrate or butyrate derivatives; nitrousoxide; hydroxyurea; Nicosan (see U.S. Pat. No. 5,800,819); Gardoschannel antagonists such as clotrimazole and triaryl methanederivatives; deferoxamine; protein C; and transfusions of blood, or of ablood substitute such as Hemospan® or Hemospan® PS (Sangart).

Administration of a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, and the second activeagents to a patient can occur simultaneously or sequentially by the sameor different routes of administration. The suitability of a particularroute of administration employed for a particular active agent willdepend on the active agent itself (e.g., whether it can be administeredorally without decomposing prior to entering the blood stream) and thedisease being treated. One route of administration for compoundsprovided herein is oral. Routes of administration for the second activeagents or ingredients are known to those of ordinary skill in the art.See, e.g., Physicians' Desk Reference (60.sup.th ed., 2006).

In another aspect, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount(s) of compounds provided herein and any optional additionalactive agents concurrently administered to the patient.

As discussed elsewhere herein, also encompassed is a method of reducing,treating and/or preventing adverse or undesired effects associated withconventional therapy including, but are not limited to, surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapyand immunotherapy. Compounds provided herein and other activeingredients can be administered to a patient prior to, during, or afterthe occurrence of the adverse effect associated with conventionaltherapy.

Cycling Therapy

In certain aspects, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in another aspect, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another aspect encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another aspect, a compound provided herein isadministered for a greater number of cycles than would typically causedose-limiting toxicity in a patient to whom a second active ingredientis not also being administered.

In another aspect, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 mg toabout 500 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 300 mg, from about0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg toabout 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about30 mg, or from about 1 mg to about 20 mg, followed by a rest.

In another aspect, a compound provided herein and a second activeingredient are administered orally, with administration of the compoundprovided herein occurring 30 to 60 minutes prior to the second activeingredient, during a cycle of four to six weeks. In another aspect, thecombination of a compound provided herein and a second active ingredientis administered by intravenous infusion over about 90 minutes everycycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This inventionencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all aspects of the invention maybe taken in conjunction with any other aspect or aspects to describeadditional aspects. It is also to be understood that each individualelement of the aspects is intended to be taken individually as its ownindependent aspect. Furthermore, any element of an aspect is meant to becombined with any and all other elements from any aspect to describe anadditional aspect.

Part III. Definitions

The examples provided in the definitions section as well as theremainder of this application are non-inclusive unless otherwise stated.They include but are not limited to the recited examples.

The compounds herein described may have asymmetric centers, geometriccenters (e.g., double bond), or both. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated. Compounds of the present invention containing anasymmetrically substituted atom may be isolated in optically active orracemic forms. It is well known in the art how to prepare opticallyactive forms, such as by resolution of racemic forms, by synthesis fromoptically active starting materials, or through use of chiralauxiliaries. Geometric isomers of olefins, C═N double bonds, or othertypes of double bonds may be present in the compounds described herein,and all such stable isomers are included in the present invention.Specifically, cis and trans geometric isomers of the compounds of thepresent invention may also exist and may be isolated as a mixture ofisomers or as separated isomeric forms. All processes used to preparecompounds of the present invention and intermediates made therein areconsidered to be part of the present invention. All tautomers of shownor described compounds are also considered to be part of the presentinvention.

“Solvate” means a compound that further includes a stoichiometric ornon-stoichiometric amount of solvent bound by non-covalentintermolecular forces. Where the solvent is water, the solvate is ahydrate.

“Alkyl” and “alkylene” includes both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms. C₁₋₆ alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, andC₆ alkyl groups. Examples of alkyl include methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

As noted previously, “alkyl” also includes deuterated alkyl. Each alkylgroup contains 2n+1 hydrogen atoms, wherein n=the number of carbonatoms. Deuterated alkyl covers alkyls groups having from 1 to 2n+1deuteriums. Deuterated C₁-6 alkyl, for example, includes Ci (d₁₋₃), C₂(d₁₋₅), C₃ (d₁₋₇), C₄ (d₁₋₉), C₅ (d₁₋₁₁), and C₆ (d₁₋₁₃), alkyl groups.

“Haloalkyl” and “haloalkylene” include alkyl groups as defined above(including deuteration), wherein one or more hydrogens are replaced by ahalogen atom selected from Cl, F, Br, and I. Examples of haloalkylinclude trifluoromethyl, 1,1,1-trifluoroethyl, and perfluoroethyl.

“Alkenyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂-6 alkenyl includes C₂, C₃, C₄, C₅, andC₆ alkenyl groups.

As noted previously, “alkenyl” also includes deuterated alkenyl. Eachalkenyl group contains 2(n−i)+1 hydrogen atoms, wherein n=the number ofcarbon atoms and i=number of double bonds. Deuterated alkenyl coversalkenyls groups having from 1 to 2(n−i)+1 deuteriums. Deuterated C₂-6alkenyl, for example, includes C₂ (d₁₋₃), C₃ (d₁₋₅), C₄ (d₁₋₇), C₅(d₁₋₉), and C₆ (d₁₋₁₁), alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl. C₂-6 Alkynyl includes C₂, C₃, C₄, C₅, and C₆alkynyl groups.

As noted previously, “alkynyl” also includes deuterated alkynyl. Eachalkynyl group contains 2(n−2i)+1 hydrogen atoms, wherein n=the number ofcarbon atoms and i=number of triple bonds. Deuterated alkenyl coversalkenyls groups having from 1 to 2(n−2i)+1 deuteriums. Deuterated C₂-6alkynyl, for example, includes C₂ (di), C₃ (d₁₋₃), C₄ (d₁₋₅), C₅ (d₁₋₇),and C₆ (d₁₋₉), alkynyl groups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in asaturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃,C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

As noted previously, “cycloalkyl” also includes deuterated cycloalkyl.Each cycloalkyl group contains 2n−1 hydrogen atoms, wherein n=the numberof carbon atoms.

Deuterated cycloalkyl covers cycloalkyl groups having from 1 to 2n−1deuteriums. Deuterated C₃₋₈ cycloalkyl, for example, includes C₃ (d₁₋₅),C₄ (d₁₋₇), C₅ (d₁₋₉), C₆ (d₁₋₁₁), C₇ (d₁₋₁₃), and C₈ (d₁₋₁₅), cycloalkylgroups.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 memberedmonocyclic, bicyclic, or tricyclic ring, wherein at least one ring, ifmore than one is present, is aromatic.

Examples of aryl include fluorenyl, phenyl, naphthyl, indanyl, andtetrahydronaphthyl.

As noted previously, “aryl” also includes deuterated aryl. For example,phenyl includes d₁₋₅ phenyl.

“Heterocycloalkyl” refers to any stable monocyclic, bicyclic, ortricyclic heterocyclic ring that is non-aromatic, and which consists ofthe specified number of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, O, and S. If theheterocycloalkyl group is bicyclic or tricyclic, then at least one ofthe two or three rings must contain a heteroatom, though both or allthree may each contain one or more heteroatoms. The N group may be N,NH, or N-substituent, depending on the chosen ring and if substituentsare recited. The nitrogen and sulfur heteroatoms may optionally beoxidized (e.g., S, S(O), S(O)₂, and N—O). The heterocycloalkyl ring maybe attached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure. A heterocycloalkyl group can have one ormore carbon-carbon double bonds or carbon-heteroatom double bonds in thering as long as the ring is not rendered aromatic by their presence. Theheterocycloalkyl rings described herein may be substituted on carbon oron a nitrogen atom if the resulting compound is stable.

As noted previously, “heterocycloalkyl” also includes deuteratedheterocycloalkyl. For example, piperidinyl and piperazino include d₁₋₁₀piperidinyl or di-9 piperazino.

Examples of heterocycloalkyl include aziridinyl, pyrrolidinyl,pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino,morpholinyl, morpholino, thiomorpholinyl, thiomorpholino,tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, andpyranyl.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 memberedmonocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic,and which consists of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, O, and S. If theheteroaryl group is bicyclic or tricyclic, then at least one of the twoor three rings must contain a heteroatom, though both or all three mayeach contain one or more heteroatoms. If the heteroaryl group isbicyclic or tricyclic, then only one of the rings must be aromatic. TheN group may be N, NH, or N-substituent, depending on the chosen ring andif substituents are recited. The nitrogen and sulfur heteroatoms mayoptionally be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heteroarylring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heteroaryl rings describedherein may be substituted on carbon or on a nitrogen atom if theresulting compound is stable.

As noted previously, “heteroaryl” also includes deuterated heteroaryl.For example, furanyl or thienyl include di-3 furanyl or di-3 thienyl.

Examples of heteroaryl includes acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,pteridinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

“Host” preferably refers to a human. It also includes other mammalsincluding the equine, porcine, bovine, feline, and canine families.

“Therapeutically effective amount” includes an amount of a compound ofthe invention that is effective when administered alone or incombination to treat the desired condition or disorder. “Therapeuticallyeffective amount” includes an amount of the combination of compoundsclaimed that is effective to treat the desired condition or disorder.The combination of compounds is preferably a synergistic combination.Synergy, as described, for example, by Chou and Talalay, Adv. EnzymeRegul. 1984, 22:27-55, occurs when the effect of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at sub-optimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased antiviral effect, or some other beneficialeffect of the combination compared with the individual components.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofthe basic residues. The pharmaceutically acceptable salts include theconventional quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. These salts canbe prepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting a purified compound ofthe invention in its free base form with a suitable organic or inorganicacid, and isolating the salt thus formed during subsequent purification.For example, such conventional non-toxic salts include, but are notlimited to, those derived from inorganic and organic acids selected from1, 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic,acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, bisulfonic,carbonic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric,glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic,hexylresorcinic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauric,laurylsulfonic, maleic, malic, mandelic, methanesulfonic, napsylic,naphthylic, nitric, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phosphoric, polygalacturonic, propionic, salicylic,stearic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric,toluenesulfonic, and valeric. (See, for example, Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.)

“Treat”, “treating” and “treatment” refer to the eradication oramelioration of a disease or disorder, or of one or more symptomsassociated with the disease or disorder. In certain embodiments, theterms refer to minimizing the spread or worsening of the disease ordisorder resulting from the administration of one or more prophylacticor therapeutic agents to a subject with such a disease or disorder.

“Prevent”, “preventing” and “prevention” refer to the prevention of theonset, recurrence or spread of a disease or disorder, or of one or moresymptoms thereof.

“Manage”, “managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof.

In certain cases, the beneficial effects that a subject derives from aprophylactic or therapeutic agent do not result in a cure of the diseaseor disorder.

“Prophylactically effective amount” of a compound is an amountsufficient to prevent a disease or disorder, or prevent its recurrence.A prophylactically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

Part IV. Exemplary General Procedures for Synthesis ofDeuterium-Enriched Compounds

The hydrogens present on the3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dioneshave different capacities for exchange with deuterium. For example,hydrogen atom R¹ is exchangeable in H₂O/D₂O. Hydrogen atoms R²-R³ andthe 3-deuterium can be exchanged under basic conditions. The remaininghydrogen atoms are not easily exchangeable for deuterium atoms, thoughsome may be depending on the specific moieties selected for R⁶ and R¹⁰.Deuterium atoms at the remaining positions may be incorporated by theuse of deuterated starting materials or intermediates via the knownsynthetic methods for the synthesis of3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-diones asdescribed in U.S. Pat. No. 7,635,700 (U.S. '700)(e.g., see section 6starting in Column 41), the contents of which are incorporated in itsentirety herein by reference. It is contemplated that the presentlydescribed deuteriated3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dionescan be prepared by incorporating deuterated starting materials into thesynthetic route of U.S. '700. Alternatively, deuterium is expected to beincorporated at the exchangeable and acidic positions of the finalcompound (e.g., R²⁻³ or the 3-position).

Scheme 1 below provides an exemplary synthetic route for preparingdeuterated3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-diones.

The compounds of the present invention can be obtained starting withamino-benzoic acid A (e.g., 2-amino-6-methyl-benzoic acid), which can beoptionally deuterated. When R⁶═H, one can react compound A with CDI(1,1′-carbonyldiimidazole), followed by the introduction of compound B,which is at least partially deuterated at Z, to yield compound D.Depending on the chosen R¹⁰, compound D could be further modified.

When Z═H in B, deuterium can be introduced into C or D by contactingeither C or D with a base (e.g., NaOD) in the presence of D₂O. Chiralchromatography or other known chiral isolation techniques can then beused to resolve the stereoisomers.

Alternatively, when R⁶ is desired to be other than H, amide C can beformed by reacting A and B. Intermediate C then allows for various R⁶groups to be introduced into compound D. For example, triethylorthoacetate can be used to form compound D, providing R⁶═CH₃. Usingtriethyl orthoformate-di should result in R⁶=D.

A number of deuterated glutamines (Compound B) have previously been madeincluding 2,3,4-trideutero-glutamine (i.e., R²=D, R⁴=D, and Z=D), whichwas made via the deuterium reduction of 6-carboxy-3(2H)-pyridazone (seeStogniew, J. Labelled Compounds and Radiopharmaceuticals 1981, 18(6),897-903), and 2,2,3,3,4 pentadeutero-glutamine (i.e., R²-R⁵=D and Z=D),which was obtained in a multi-step synthesis (see Blomquist, J. Org.Chem. 1966, 12, 4121-27). Stogniew also notes that the5-mono-deutero-glutamine could be obtained through deuterium reductionof 4,5-dihydro-6-carboxy-3(2H)-pyridazone.

If non-stereospecific glutamine is used or if the stereospecificity islost during the reaction, it is expected that the resulting deuteratedracemic mixture will be separable using known isolation techniques(e.g., chiral chromatography).

Scheme 2 below provides an exemplary synthetic route for preparingstereospecific deuterated3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-diones.

When R¹⁰ is an amino group or amino derivative, one can arrive atdeuterated3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dionesby starting with a benzo[d][1,3]oxazin-4-one as shown in Scheme 3.

The 5-nitro-2-methyl-benzo[d][1,3]oxazin-4-one, E, can be prepared from2-amino-6-nitrobenzoic acid and acetic anhydride. Reacting theoxazin-4-one with compound B should provide the nitro-derivative of D.The amine, R¹⁰═NH₂, should be obtained through hydrogenation. Furthermodification of the amino group can then be made.

When R¹⁰ is a (CH₂)_(n)-amino moiety, one can use a 6-protected aminostarting material as shown in Scheme 4.

2-amino-6-(tert-butoxycarbonylamino-methyl)-benzoic acid, F, can be madeas described in U.S. '700, columns 61-62. F can then be reacted with acarbonyl compound (e.g., acetyl chloride) and the resulting compoundreacted with B to arrive at D. The amino protecting group can be removedand further modification of the amine can be performed.

Scheme 5 depicts a route to 5-amino-quinazolinones.

Scheme 6 depicts a route to 5-methyl-quinazolinones.

Part V. Dosages and Formulations

Dosages of a compound provided herein, or stereoisomer orpharmaceutically acceptable salt thereof, vary depending on factors suchas: specific indication to be treated and/or managed; age and conditionof a patient; and amount of second active agent used, if any.

Generally, a compound provided herein, or stereoisomer orpharmaceutically acceptable salt thereof, may be used in an amount offrom about 0.1 mg to about 500 mg per day, and can be adjusted in aconventional fashion (e.g., the same amount administered each day of thetreatment and/or management period), in cycles (e.g., one week on, oneweek off), or in an amount that increases or decreases over the courseof treatment and/or management. In other aspects, the dose can be fromabout 1 mg to about 300 mg, from about 0.1 mg to about 150 mg, fromabout 1 mg to about 200 mg, from about 10 mg to about 100 mg, from about0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about 10 mgto about 50 mg, from about 20 mg to about 30 mg, or from about 1 mg toabout 20 mg.

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof.Pharmaceutical compositions and dosage forms can further comprise one ormore excipients.

Pharmaceutical compositions and dosage forms provided herein cancomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are described above.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

In another aspect of the present invention, the pharmaceuticalcompositions and dosage forms comprise one or more excipients. Suitableexcipients are well known to those skilled in the art of pharmacy, andnon-limiting examples of suitable excipients are provided herein.Whether a particular excipient is suitable for incorporation into apharmaceutical composition or dosage form depends on a variety offactors well known in the art including, but are not limited to, the wayin which the dosage form will be administered to a patient. For example,oral dosage forms such as tablets may contain excipients not suited foruse in parenteral dosage forms. The suitability of a particularexcipient may also depend on the specific active ingredients in thedosage form. For example, the decomposition of some active ingredientsmay be accelerated by some excipients such as lactose, or when exposedto water. Active ingredients that comprise primary or secondary aminesare particularly susceptible to such accelerated decomposition.Consequently, provided are pharmaceutical compositions and dosage formsthat contain little, if any, lactose other mono- or di-saccharides. Asused herein, the term “lactose-free” means that the amount of lactosepresent, if any, is insufficient to substantially increase thedegradation rate of an active ingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In another aspect,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in another aspect, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, dose containers (e.g.,vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but are not limited to, the route by which it is to beadministered to patients. In another aspect, dosage forms comprise acompound provided herein in an amount of from about 0.10 to about 500mg. Examples of dosages include, but are not limited to, 0.1, 1, 2, 5,7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400,450, or 500 mg.

In another aspect, dosage forms comprise the second active ingredient inan amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound provided herein, and any optionaladditional active agents concurrently administered to the patient.

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but are not limitedto, tablets (e.g., chewable tablets), caplets, capsules, and liquids(e.g., flavored syrups). Such dosage forms contain predetermined amountsof active ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In another aspect, the present invention provides oral dosage forms thatare tablets or capsules, in which case solid excipients are employed. Inanother aspect, the tablets can be coated by standard aqueous ornonaqueous techniques. Such dosage forms can be prepared by any of themethods of pharmacy. In general, pharmaceutical compositions and dosageforms are prepared by uniformly and intimately admixing the activeingredients with liquid carriers, finely divided solid carriers, orboth, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in anotheraspect, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. Inanother aspect, pharmaceutical compositions comprise from about 0.5 toabout 15 weight percent of disintegrant, or from about 1 to about 5weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a Syloid® silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPiano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In another aspect, the present invention provides a solid oral dosageform comprising a compound provided herein, anhydrous lactose,microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,colloidal anhydrous silica, and gelatin.

Active ingredients provided herein can also be administered bycontrolled release means or by delivery devices that are well known tothose of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767,5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of whichis incorporated in its entirety herein by reference. Such dosage formscan be used to provide slow or controlled-release of one or more activeingredients using, for example, hydroxypropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active agents provided herein. In anotheraspect, the present invention procies single unit dosage forms suitablefor oral administration such as, but are not limited to, tablets,capsules, gelcaps, and caplets that are adapted for controlled-release.

Controlled-release pharmaceutical products improve drug therapy overthat achieved by their non-controlled counterparts. In another aspect,the present invention provides the use of a controlled-releasepreparation in medical treatment characterized by a minimum of drugsubstance being employed to cure or control the condition in a minimumamount of time. Advantages of controlled-release formulations includeextended activity of the drug, reduced dosage frequency, and increasedpatient compliance. In addition, controlled-release formulations can beused to affect the time of onset of action or other characteristics,such as blood levels of the drug, and can thus affect the occurrence ofside (e.g., adverse) effects.

In another aspect, the controlled-release formulations are designed toinitially release an amount of drug (active ingredient) that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release of other amounts of drug to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In another aspect, in order to maintain a constant level of drug in thebody, the drug can be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled release of an active ingredient can be stimulated by variousconditions including, but are not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

Parenteral dosage forms can be administered to patients by variousroutes including, but are not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial.Administration of a parenteral dosage form bypasses patients' naturaldefenses against contaminants, and thus, in these aspects, parenteraldosage forms are sterile or capable of being sterilized prior toadministration to a patient. Examples of parenteral dosage formsinclude, but are not limited to, solutions ready for injection, dryproducts ready to be dissolved or suspended in a pharmaceuticallyacceptable vehicle for injection, suspensions ready for injection, andemulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butare not limited to, Sodium Chloride Injection, Ringer's Injection,Dextrose Injection, Dextrose and Sodium Chloride Injection, and LactatedRinger's Injection; water-miscible vehicles such as, but are not limitedto, ethyl alcohol, polyethylene glycol, and polypropylene glycol; andnonaqueous vehicles such as, but are not limited to, corn oil,cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropylmyristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated in itsentirety herein by reference.

Topical and mucosal dosage forms provided herein include, but are v^(n)+limited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington 's Pharmaceutical Sciences, 16thand 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In another aspect,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1, 3-diol, isopropylmyristate, isopropyl palmitate, mineral oil, and mixtures thereof toform solutions, emulsions or gels, which are nontoxic andpharmaceutically acceptable. Moisturizers or humectants can also beadded to pharmaceutical compositions and dosage forms. Examples ofadditional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, EastonPa. (1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other aspects, stearates can serve as a lipidvehicle for the formulation, as an emulsifying agent or surfactant, oras a delivery-enhancing or penetration-enhancing agent. In otheraspects, salts, solvates, prodrugs, or stereoisomers of the activeingredients can be used to further adjust the properties of theresulting composition.

In another aspect, the active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another aspect, provided are kits which can simplifythe administration of appropriate amounts of active ingredients.

In another aspect, the present invention provides a kit comprising adosage form of a compound provided herein. Kits can further compriseadditional active ingredients such as oblimersen (Genasense©),melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan,taxotere, IFN, COX-2 inhibitor, pentoxifylline, ciprofloxacin,dexamethasone, IL-2, IL-8, IL-18, Ara-C, vinorelbine, isotretinoin, 13cis-retinoic acid, or a pharmacologically active mutant or derivativethereof, or a combination thereof. Examples of the additional activeingredients include, but are not limited to, those disclosed herein.

In other aspects, the kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but are not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but are not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but are notlimited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyloleate, isopropyl myristate, and benzyl benzoate.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1: Synthesis ofrac-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dioneStep 1. Synthesis of 2-Methyl-5-nitro-4H-3,1-benzoxazin-4-one

2-Amino-6-nitrobenzoic acid (25.0 g, 137 mmol) was mixed with aceticanhydride (50 mL, 529 mmol) and the resulting mixture was heated to 120°C. by placing the reaction vessel containing this mixture in an oil bathfor 2 hours, while monitoring reaction progress by HPLC. Next, thereaction mixture was cooled, and partially concentrated by evaporationunder a stream of dry nitrogen. The reaction mixture was then dilutedwith 100 mL diethyl ether and cooled in a refrigerator overnight. Theresulting crystals were filtered and rinsed with diethyl ether (50 mL)to provide the title compound (25.3 g, 123 mmol, 89%) as a tan,crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ 7.91 (t, J=8.0 Hz, 1H),7.57 (dd, J=7.8, 1.01 Hz, 1H), 7.53 (dd, J=8.3, 1.0 Hz, 1H), 2.53 (s,3H). MS (ESI+) calc. for [C₉H₆N₂O₄+H]⁺ 207.2, found 207.2.

Step 2. Synthesis of 2-Acetamido-6-nitrobenzoic Acid

The starting material (24.7 g, 120 mmol) was dispersed in water (216 mL)and the resulting mixture was heated to reflux for 30 min. Upon coolingthe reaction mixture, crystallization began. Next, the reaction mixturewas placed in a refrigerator for 18 hours to complete crystallization.The crystalline material was isolated by filtration and dried undervacuum to give the title compound (24.3 g, 108 mmol, 90.5%) as a paleyellow, crystalline solid. ¹H NMR (300 MHz, MeOH-d₄) δ 8.49 (d, J=8.1Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 8.01 (t, J=8.2 Hz, 1H), 2.53 (s, 3H).MS (ESI−) calc. for [C₉H₈N₂O₅—H]⁻ 223.0, found 223.1.

Step 3. Synthesis ofrac-2-Acetamido-N-(2,6-dioxopiperidin-3-yl)-6-nitrobenzamide

The starting acid (3.10 g, 13.8 mmol) was mixed withhydroxybenzotriazole (HOBt, 2.12 g of the hydrate, 13.8 mmol) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 2.54g, 13.3 mmol), under a nitrogen atmosphere. N,N-dimethylformamide (DMF,21.4 mL) was added and the mixture was stirred for 30 minutes at roomtemperature. rac-3-Aminopiperidine-2,6-dione hydrochloride (5.01 g, 30.4mmol) was added, followed by N,N-diisopropylethylamine (DIEA, 9.63 mL,55.3 mmol). The reaction mixture was stirred at 20° C., while monitoringby HPLC. After 24 hours, the reaction mixture showed approximately 40%conversion to the desired product containing some remaining startingacid, but no amine. Then, the reaction mixture was slowly poured into200 mL water with vigorous stirring. After 20 minutes, a whiteprecipitate began to form. The mixture was placed in the refrigeratorfor 18 hours. Then, the precipitate was isolated by filtration. Thefilter cake was washed with 50 mL ether, and air dried to provide thetitle compound (1.60 g, 4.79 mmol, 35%) as a white powder. ¹H NMR (300MHz, DMSO-d6) δ 11.16 (s, 1H), 9.40 (s, 1H), 9.34 (d, J=8.0 Hz, 1H),8.53 (d, J=7.5 Hz, 1H), 7.89 (dd, J=8.2, 0.98 Hz, 1H), 7.66 (t, J=8.3Hz, 1H), 4.79 (m, 1H), 2.85 (m, 1H), 2.59 (m, 1H), 2.21 (m, 1H), 2.20(s, 3H), 2.03 (m, 1H). MS (ESI−) calc. for [C₁₄H₁₄N₄O₆—H]⁻ 333.3, found333.2.

Step 4. Synthesis ofrac-3-(2-Methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)-(3_²H)-piperidine-2,6-dione

rac-2-Acetamido-N-(2,6-dioxopiperidin-3-yl)-6-nitrobenzamide (4.50 g,13.5 mmol) was dispersed in anhydrous acetonitrile (70.3 mL) under anitrogen atmosphere. Triethylamine (88.2 mL, 633 mmol) was added viasyringe, followed by the dropwise addition of chlorotrimethylsilane(25.6 mL, 202 mmol). The reaction mixture was warmed to 75° C. and thereaction was monitored by HPLC. After 42 hours, 85% of the desiredproduct was present. The reaction mixture was cooled to 20° C., stirredrapidly, and quenched with deuterium oxide (100 mL, 5.55 moles). Thereaction mixture was stirred for an additional 20 minutes and a whiteprecipitate formed. Next, the reaction mixture was cooled in arefrigerator for 4 hours and filtered to provide the title compound(2.25 g, 7.1 mmol, 53%) as an off-white, crystalline solid. ¹H NMR (300MHz, DMSO-d₆) δ 11.07 (s, 1H), 7.98 (t, J=7.6 Hz, 1H), 7.83 (2 dd,J=14.4, 8.0, 1.2 Hz, 2H), 2.82 (m, 1H), 2.67 (s, 3H), 2.56 (m, 2H), 2.18(m, 1H). MS (ESI−) calc. for [C₁₄H₁₁[²H]N₄O₅—H]⁻ 316.1, found 316.0.

Step 5. Synthesis ofrac-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3_²H)-piperidine-2,6-dione

3-(2-Methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(2.25 g, 7.09 mmol) was dispersed in DMF (60 mL) in a Parr bottle andpalladium hydroxide (500 mg, 20% active catalyst, 50 wt % water) wasadded. The bottle was then placed under 50 psi hydrogen pressure andshaken for 2 hours at 21° C. The reaction mixture was analyzed by HPLC,which showed a major peak for the desired product and no startingmaterial. The reaction mixture was treated with activated carbon andfiltered through a plug of silica gel overlain with 1 cm of sodiumsulfate. The plug was washed with 50 mL acetonitrile and the filtratewas evaporated under high vacuum to give a black gum. This material wasdissolved in 50 mL of acetonitrile and filtered through a Magnesol®plug, then washed with 100 mL of acetonitrile.

The filtrate was placed in a freezer for 48 hours, and then filtered toafford smoky grey crystals, which were washed with diethyl ether (50 mL)and air dried for 3 hours to give the title compound (1.63 g, 5.67 mmol,80%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 7.37 (t, J=8.1 Hz, 1H),7.03 (br s, 2H), 6.58 (dd, J=11.2, 8.1 Hz, 2H), 2.83 (m, 0.92H), 2.60(m, 2H), 2.53 (s, 3H), 2.14 (m, 0.92H). MS (ESI+) calc. for[C₁₄H₁₃[²H]N₄O₃+H]⁺ 288.1, found 288.2.

¹H NMR (400 MHz, pyridine-d₅) δ 13.14 (br s, 1H), 7.69 (br s, 2H), 7.46(t, J=8.1 Hz, 1H), 7.06 (dd, J=7.8, 0.9 Hz, 1H), 6.78 (dd, J=8.2, 0.9Hz, 1H), 5.39 (dd, J=11.5, 5.7 Hz, 0.06H, residual C(3)H, ca. 94% Dincorporation], 3.12 (m, 1H), 2.94 [m, 1.81H, C(5)H, ca. 19% Dincorporation], 2.17 (s, 3H), 2.19 (ddd, J=3.2, 4.6, 12.6, 1H).

¹H NMR in pyridine-d₅ indicates approximately 94% deuteriumincorporation at C(3), and approximately 19% deuterium incorporation atC(5). Mass spectroscopic analysis indicates 4% protonated, 80%mono-deuterated, and 16% bis-deuterated.

Example 2: Separation of Pure Enantiomers ofrac-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dioneand Pure Enantiomers ofrac-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dionePart I: Separation of Enantiomers fromrac-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione

rac-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione(136 mg, 0.475 mmol) was dissolved in 10 mL ofacetonitrile:isopropanol:methanol (5:3:2 v/v/v). The enantiomers wereseparated by chiral supercritical fluid chromatography on a ChiralPakAD-H column (21×250 mm) using a mobile phase of 37% isopropanol incarbon dioxide (flow rate: 70 mL/min; 1 mL injected per run). Compoundswere detected by UV at 254 nm. Fractions containing the compounds werepooled and evaporated. Purity and enantiomeric excess (% ee=% enantiomer1−% enantiomer 2) were determined by analytical supercritical fluidchromatography on a ChiralPak AD-H column (4.6×100 mm) using the sameeluent. The enantiomers, peaks 1 and 2, identified as(−)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dioneand(+)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione,respectively, were dried under vacuum and stored in the freezer. Yield:134.1 mg overall (0.468 mmol, 98.6%) as 67.3 mg peak 1 (0.235 mmol,99.7% purity and 99.4% ee) and 66.8 mg peak 2 (0.233 mmol, 99.8% purityand 99.6% ee).

Part II: Separation of Enantiomers fromrac-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3_²H)-piperidine-2,6-dione

The enantiomers ofrac-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)piperidine-2,6-dionewere separated using the chromatographic method described in Part Iabove. Separation of 0.948 g ofrac-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)piperidine-2,6-dione(3.3 mmol) gave the two pure enantiomers in 726.7 mg (2.53 mmol, 77%)overall yield. Purity and enantiomeric excess were determined bysupercritical fluid analytical chromatography as described above.Deuterium content was measured by LC/MS-MS and optical rotation wasmeasured in N,N-dimethylformamide (DMF) at room temperature.

(−)-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)piperidine-2,6-dione:340 mg (1.18 mmol); 99.8% purity; 99.6% ee; LC-MS: 288.3 (M+1) (90.3%deuterium); ¹H NMR (200 MHz, DMSO-d₆) δ 10.95 (s, 1H), 7.33 (t, J=8 Hz,1H), 6.99 (br s, 2H), 6.56 (d, J=8 Hz, 1H), 6.52 (d, J=6 Hz, 1H), 5.1(m, 0.12H, residual C(3)H, approximately 88% deuterium incorporation),2.75 (m, 6H), 2.11 (m, 1H); optical rotation [α]_(D)=−47.2° (c 1.0,19.3° C., DMF).

(+)-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)piperidine-2,6-dione:386.7 mg (1.35 mmol); 99.2% purity; 98.4% ee; LC-MS: 288.3 (M+1) (92.6%deuterium); ¹H NMR (300 MHz, DMSO-d6) δ 11.04 (s, 1H), 7.40 (t, J=8.0Hz, 1H), 7.0 (br s, 2H), 6.61 (d, J=8.0, 2H), 5.2 (m, 0.14H, residualC(3)H, approximately 86% deuterium incorporation), 2.82 (m, 1H), 2.61(m, 5H), 2.15 (m, 1H); optical rotation [α]_(D)=+43.35° (c 1.0, 19.3°C., DMF).

Example 3: Mouse and Human Plasma Stability of(+)-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione,(−)-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione,andrac-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione

(+)- and(−)-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dioneandrac-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(87% deuterium content at the C3-position and no detectable deuterium atthe C5-position, 50:50 racemic mixture of (+)- and (−)-deuteratedenantiomers) were incubated in CD-1 mouse plasma (K₃EDTA asanticoagulant) or human plasma (K₃EDTA as anticoagulant) at 37° C. induplicates. Aliquots were removed at t=0, 0.5, 1, 2, 6, 8, 24, 48, and96 h.

Plasma proteins were precipitated by addition of acetonitrile containinginternal standard (ISTD, tolbutamide) and the supernatants were analyzedsemi-quantitatively by LC/MS-MS with elution on a chiral column (DaicelChiralPak IE-3) for the separation of enantiomers (isocratic method of20:80 v/v 0.1% acetic acid in water and acetonitrile). Peak areas forthe deuterated enantiomers (+)- and(−)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dionewere normalized to the ISTD and corrected for the isotopic peak of thecorresponding protonated enantiomer, (+)- and(−)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dionerespectively, if present. Corrected data were analyzed and plotted usingMicrosoft Excel 2013 (Microsoft Corp, Redmond, Wash.) and the ExcelSolver.

Scheme 1 below illustrates the possible reactions in a solution ofdeuterated racemate. The deuterium in both enantiomers, d+ and d−, canbe lost by D/H exchange to give both protonated enantiomers, h+ and h−with rate constants k_(D++), k_(D+−), k_(D−+), k_(D−−). At the sametime, the protonated enantiomers h+ and h−, can exchange, withenantiomerization rate constants k⁺⁻ and k⁻⁺. All four compounds canalso degrade with potentially different degradation rate constantsk_(h+d), k_(h−d), k_(d+d), k_(d−d).

Human and mouse plasma data were analyzed independently. Independentanalyses of the data for h+ and h− were performed first and the averagerate constants k+− and k−+ from these two fits were calculated and usedas constants in the fitting of the stability data of the deuteratedracemate. Calculated concentrations were obtained through numericalapproximation of differential equations (1) and (2) for the stabilitystudies of h+ and h− and equations (3) to (6) for the stability study ofdeuterated racemate (50:50 d+:d−) by the Euler method (equation (7)).The step between calculated time points was minimized in order tominimize the local error (proportional to the square of the step size)and the global error (proportional to the step size).

To limit the complexity of calculations, the assumption was made thatdegradation was not affected by the isotopic substitution or thechirality, hence k_(h+d)=k_(h−d)=h_(d+d)=k_(d−d)=k_(d). The averagedegradation rate constant obtained by fitting the data for h+ and h− wasused in the fit of the stability data of the deuterated racemate. Dataanalysis was performed in Microsoft Excel 2013, using the SolverGeneralized Reduced Gradient Nonlinear method with central derivativesto minimize the sum of sums of weighted Δ², square of difference betweenISTD-normalized experimental data and calculated value, divided by theexperimental data.

$\begin{matrix}{{\frac{d\left\lbrack {h +} \right\rbrack}{dt} = {{- {\left( {k_{+ -} + k_{d}} \right)\left\lbrack {h +} \right\rbrack}} + {k_{- +}\left\lbrack {h -} \right\rbrack}}}{\frac{d\left\lbrack {h -} \right\rbrack}{dt} = {k + {- \left\lbrack {h +} \right\rbrack} - {\left( {k_{- +} + k_{d}} \right)\left\lbrack {h -} \right\rbrack}}}{\frac{d\left\lbrack {h +} \right\rbrack}{dt} = {{- {\left( {k_{+ -} + k_{d}} \right)\left\lbrack {h +} \right\rbrack}} + {k_{- +}\left\lbrack {h -} \right\rbrack} + {k_{D + +}\left\lbrack {d +} \right\rbrack} + {k_{D - +}\left\lbrack {d -} \right\rbrack}}}{\frac{d\left\lbrack {h -} \right\rbrack}{dt} = {{k_{+ -}\left\lbrack {h +} \right\rbrack} - {\left( {k_{- +} + k_{d}} \right)\left\lbrack {h -} \right\rbrack} + {k_{D + -}\left\lbrack {d +} \right\rbrack} + {k_{D--}\ \left\lbrack {d -} \right\rbrack}}}{\frac{d\left\lbrack {d +} \right\rbrack}{dt} = {- {\left( {k_{D + +} + k_{D + -} + k_{d}} \right)\left\lbrack {d +} \right\rbrack}}}{\frac{d\left\lbrack {d -} \right\rbrack}{dt} = {- {\left( {k_{D--} + k_{D - +} + k_{d}} \right)\left\lbrack {d -} \right\rbrack}}}} & {{Equations}\mspace{14mu}\text{1-6}}\end{matrix}$

where [h+], [h−], [d+], [d−] are the concentrations of both protonatedand deuterated enantiomers, k⁺⁻ and k⁻⁺ are the rate constants for theenantiomerization reactions [h+] to [h−] and [h−] to [h+] respectively,k_(D++), k_(D+−), k_(D−+), and k_(D−−) are the rate constants for theD/H exchange reactions [d+] or [d−] to [h+] or [h−], and k_(d) is therate constant for the degradation of all four compounds

$\begin{matrix}{\lbrack X\rbrack_{t\; 2} = {\lbrack X\rbrack_{t\; 1} + {\left( {t_{2} - t_{1}} \right)\left\lbrack {d\lbrack X\rbrack} \right\rbrack}_{t\; 1}}} & {{Equation}\mspace{14mu} 7}\end{matrix}$

where [X]_(ti) is the concentration of either enantiomer at time ti, t1is a time at which [X] is known, t2 is a time at which [X] iscalculated, and [d[X]]_(t1) is the calculated value of the differentialequation at time t1.

The observed and fitted data are shown in FIGS. 1-3 for human plasma.The observed and fitted data are shown in FIGS. 4-6 for mouse plasma.Fitted parameters are presented in Table 1.

TABLE 1 Rate Constants and Calculated Half-life (t_(1/2)) for the InVitro Stability of h−, h+, and d-rac in Human and Mouse Plasma at 37° C.Obtained by Fitting Experimental Data to Equations 1 to 6. SpeciesCompound D++ D+− D−+ D−− +−* −+* d** human d-rac k (h⁻¹) 0.084 0 0 0.1340.264 0.195 0.0905 t_(1/2) (h) 8.3 5.2 2.6 3.6 7.8 h− k (h⁻¹) — — — —0.231 0.169 0.0845 t_(1/2) (h) — — 3.0 4 1 8.2 h+ k (h⁻¹) — — — — 0.2970.220 0.0965 t_(1/2) (h) — — 2.3 3.2 7.2 mouse d-rac k (h⁻¹) 0.04660.00109 0.0166 0.0380 0.0662 0.0959 0.0533 t_(1/2) (h) 14.5 12.7 10.57.2 13.0 h− k (h⁻¹) — — — — 0.0722 0.0730 0.0544 t_(1/2) (h) — — 9.6 9.512.7 h+ k (h⁻¹) — — — — 0.0603 0.119 0.0523 t_(1/2) (h) — — 11.5 5.813.3 *enantiomerization rate constants used in analysis of stability ofdeuterated racemate d-rac = average of enantiomerization rate constantsobtained by fitting data for stability of h− and h+. **degradation rateconstant for the enantiomers of d-rac = average of degradation rateconstants for h− and h+.

Example 4: Pharmacokinetics ofrac-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione(abbreviated “h-rac”),(+)-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(abbreviated “d+”), and(−)-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(abbreviated “d−”)

Female CB.17 SCID mice (8-12 weeks of age) were administered a singledose of protonated racemate (h-rac, 30 mg/kg), d− (15 mg/kg), or d+ (15mg/kg) by oral gavage. Deuterated enantiomers (i.e., d− and d+) used inthis study contain ˜10% of the corresponding protonated enantiomer.Blood was collected into potassium EDTA (K₂EDTA) containers by terminalcardiac puncture under carbon dioxide anesthesia from N=3 per group pertime point at 0.25, 0.5, 1, 2, 4, 8, and 24 h post-dose. Plasma wasisolated, frozen, and stored until ready for analysis.

Samples were prepared for quantitative analysis by liquid-liquidextraction in methyl-t-butylether (MTBE) with ondansetron as internalstandard (ISTD). MTBE was evaporated under nitrogen flow and sampleswere reconstituted in 1% acetic acid in water/acetonitrile (20/80).Analysis was performed by chiral LC/MS-MS on a Daicel ChiralPak IE-3column using an isocratic LC method of 0.1% acetic acid in water andacetonitrile (20:80 v/v). ISTD-normalized peak areas for deuteratedenantiomers d- and d+were corrected from interference from naturallyoccurring isotopes of the protonated analytes. Concentrations wereobtained by interpolation on standard curves prepared in mouse plasmausing standard solutions of the analytes.

Data was plotted in Excel 2013 (Microsoft Corp, Redmond, Wash.) andanalyzed within Excel using the PKSolver add-in (version 2.0, asdescribed in Zhang Y. et al Comput. Methods Programs Biomed. 99 (2010),306-314) to determine pharmacokinetic parameters including exposure (asarea under the curve, AUC) and elimination half-life (tv2).Pharmacokinetic profiles are shown in FIGS. 7-9 and selectedpharmacokinetic parameters are presented in Table 1 below.

TABLE 1 Select Pharmacokinetic (PK) Parameters for Enantiomers ofProtonated and Deuterated3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione.Compound PK Compound Adimnistered by Oral Gavage (dosage) AnalyzedParameter h-rac (30 mg/kg) d − (15 mg/kg) d + (15 mg/kg) h− t_(1/2) (h)2.1 1.2 N/A AUC (ng.h/mL) 22500 6160 993 h+ t_(1/2) (h) 2.0 N/A 1.0 AUC(ng.h/mL) 35900 1180 6120 d− t_(1/2) (h) — 1.2 N/A AUC (ng.h/mL) — 44100661 d+ t_(1/2) (h) — N/A 1.1 AUC (ng.h/mL) — 898 63600

The experimental results indicate that elimination is fast (tv2=1-2h)for both protonated and deuterated enantiomers of3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione,irrespective of chirality. Exposure to the enantiomers of the protonatedmolecule is stereoselective with h− representing 39% of the totalexposure. Exposure to the deuterated enantiomers shows the samestereoselectivity. Exposure to the protonated enantiomers h− and h+ uponadministration of the deuterated enantiomers represents about 10-14% ofthe total exposure, corresponding to the amount of protonated compoundin the dosed material. Little to no D/H exchange is evidenced in thepharmacokinetic parameters, and exposure to the dosed enantiomer(protonated and deuterated) represents 96-98% of the total exposure.

Example 5: Efficacy of(+)-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(abbreviated “d+”) and(−)-3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione(abbreviated “d−”) in Human Multiple Myeloma H929 Cell Line in FemaleCB.17 SCID Mice

Female CB.17 SCID mice (8-12 weeks of age, N=60) were administered 1×10⁷H929 tumor cells in 50% Matrigel subcutaneously in their flank (0.2mL/mouse). Animals were returned to their cages and tumor growth wasmonitored. Tumor size was reported as tumor volume (Vol) calculated asVol=12 (L*W²), where L and W are the length and width of the tumor asmeasured by caliper (L>W). A pair match was performed when tumorsreached an average size of 100-150 mm³ and the animals were divided into6 treatment groups of N=10 animals each.

Animals were treated daily by oral gavage (10 mL/kg) with vehicle, d−(1.5 or 15 mg/kg), d+ (1.5 or 15 mg/kg), or h-rac (racemic mixture ofprotonated enantiomers h− and h+; 3 mg/kg). The compound h-rac wasadministered at twice the dose of the deuterated enantiomers since itcontains 50% (i.e., 1.5 mg/kg) of each enantiomer. Body weightmeasurements were taken daily for the first week then biweekly. Tumorsizes were measured by caliper biweekly. The study was terminated after23 days of dosing, then all animals were euthanized.

Tumor volume as a function of time is shown in FIG. 10. As the resultsin FIG. 10 show, deuterated enantiomer d− was more potent at limitingtumor growth at both doses than h-rac (i.e., the racemic mixture ofcompound not enriched in deuterium). The other deuterated enantiomer(i.e., d+) was less efficacious than d−, and efficacy for d+ wasobserved only at the highest dose of d+.

INCORPORATION BY REFERENCE

All references listed herein are individually incorporated in theirentirety by reference.

EQUIVALENTS

Numerous modifications and variations of the invention are possible inlight of the above teachings. It is therefore to be understood thatwithin the scope of the appended claims, the invention may be practicedotherwise that as specifically described herein.

1. A deuterium-enriched compound of Formula I:

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein: Z is H or D, provided that the abundance of deuteriumin Z is at least 30%; R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ areindependently selected from H and D; R⁶ is selected from: H; D;—(CH₂)_(n)OH; phenyl; —O(C₁-C₆)alkyl; and (C₁-C₆)alkyl optionallysubstituted with one or more halo; R¹⁰ is selected from: H; D; halo;—(CH₂)_(n)OH; (C₁-C₆)alkyl optionally substituted with one or more halo;(C₁-C₆)alkoxy optionally substituted with one or more halo; and—(CH₂)_(n)NHR^(a); R^(a) is selected from: H; D; (C₁-C₆)alkyl optionallysubstituted with one or more halo; —(CH₂)_(n)-(6 to 10 membered aryl);—C(O)(CH₂)_(n)-(6 to 10 membered aryl); —C(O)(CH₂)_(n)-(6 to 10 memberedheteroaryl); —C(O)(C₁-C₈)alkyl optionally substituted with one or morehalo; —C(O)(CH₂)_(n)—(C₃-C₁₀-cycloalkyl); —C(O)(CH₂)_(n)—NR^(b)R^(c),—C(O)(CH₂)_(n)—O—(C₁-C₆)alkyl; and, —C(O)(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10membered aryl); wherein the aryl and heteroaryl are optionallysubstituted with one or more groups selected from: halo; —SCF₃;(C₁-C₆)alkyl optionally substituted with one or more halo; and(C₁-C₆)alkoxy optionally substituted with one or more halo; R^(b) andR^(c) are each independently selected from: H; D; (C₁-C₆)alkyloptionally substituted with one or more halo; (C₁-C₆)alkoxy optionallysubstituted with one or more halo; and 6 to 10 membered aryl; the arylbeing optionally substituted with one or more groups selected from:halo; (C₁-C₆)alkyl optionally substituted with one or more halo; and(C₁-C₆)alkoxy optionally substituted with one or more halo;alternatively, R¹⁰ is selected from R^(10a), R^(10b), and R^(10c);R^(10a) is selected from: H; D; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyloptionally substituted with one or more halo; and (C₁-C₆)alkoxyoptionally substituted with one or more halo;R^(10b)=—(CH₂)_(n)—NHR^(d); R^(10c)=—(CH₂)_(n)—NHR^(g); R^(d) isselected from: H; D; —(C₁-C₆)alkyl optionally substituted with one ormore halo; —C(O)(C₁-C₈)alkyl optionally substituted with one or morehalo; —C(O)(CH₂)_(n)(C₃-C₁₀-cycloalkyl); —C(O)(CH₂)_(n)NR^(e)R^(f); and,—C(O)(CH₂)_(n)O(C₁-C₆)alkyl. R^(e) and R^(f) are each independentlyselected from: hydrogen; (C₁-C₆)alkyl optionally substituted with one ormore halo; and (C₁-C₆)alkoxy optionally substituted with one or morehalo; R^(g) is selected from: —C(O)(CH₂)_(n)NHR^(h); —(CH₂)_(n)-(6 to 10membered aryl); —C(O)(CH₂)_(n)-(6 to 10 membered aryl);—C(O)(CH₂)_(n)-(6 to 10 membered heteroaryl); and,—C(O)(CH₂)_(n)O(CH₂)_(n)-(6 to 10 membered aryl), wherein the aryl andheteroaryl are optionally substituted with one or more groups selectedfrom: halo; —SCF₃; (C₁-C₆)alkyl optionally substituted with one or morehalo; and, (C₁-C₆)alkoxy substituted with one or more halo; R^(h) isselected from: 6 to 10 membered aryl optionally substituted with one ormore groups selected from: halo; (C₁-C₆)alkyl optionally substitutedwith one or more halo; and, (C₁-C₆)alkoxy optionally substituted withone or more halo; n is independently selected from selected from 0, 1,and 2; and a hydrogen atom present in any substituent is optionallyreplaced by D.
 2. The deuterium-enriched compound of claim 1, whereinthe compound is

having an enantiomeric excess of at least 90%, or a pharmaceuticallyacceptable salt thereof.
 3. The deuterium-enriched compound of claim 2,wherein the abundance of deuterium in Z is at least 80%.
 4. Thedeuterium-enriched compound of claim 2, wherein the abundance ofdeuterium in Z is at least 90%.
 5. The deuterium-enriched compound ofclaim 2, wherein the abundance of deuterium in Z is at least 95%.
 6. Thedeuterium-enriched compound of claim 5, wherein the compound has anenantiomeric excess of at least 95%.
 7. The deuterium-enriched compoundof claim 1, wherein the compound is

having an enantiomeric excess of at least 90%, or a pharmaceuticallyacceptable salt thereof.
 8. The deuterium-enriched compound of claim 7,wherein the abundance of deuterium in Z is at least 80%.
 9. Thedeuterium-enriched compound of claim 7, wherein the abundance ofdeuterium in Z is at least 90%.
 10. The deuterium-enriched compound ofclaim 7, wherein the abundance of deuterium in Z is at least 95%. 11.The deuterium-enriched compound of claim 10, wherein the compound has anenantiomeric excess of at least 95%.
 12. The deuterium-enriched compoundof claim 1, wherein the compound is a deuterium-enriched compound ofFormula Ia or Ib:

and pharmaceutically acceptable salts and solvates thereof, wherein thecompound has an enantiomeric excess, with respect to the C—Z carbon, ofat least 5%.
 13. The deuterium-enriched compound of claim 1, wherein thecompound is a deuterium-enriched compound of Formula Ic or Id:

and pharmaceutically acceptable salts and solvates thereof, wherein thecompound has an enantiomeric excess, with respect to the C—Z carbon, ofat least 5%.
 14. The deuterium-enriched compound of claim 1, wherein thecompound is a deuterium-enriched compound of Formula Ie or If:

and pharmaceutically acceptable salts and solvates thereof, wherein thecompound has an enantiomeric excess, with respect to the C-D carbon, ofat least 5%.
 15. A deuterium-enriched compound of claim 12, whereinR¹⁰═R^(10a) and pharmaceutically acceptable salts and solvates thereof.16-30. (canceled)